Substituted 6-membered aryl or heteroaryl allosteric modulators of nicotinic acetylcholine receptors

ABSTRACT

The present disclosure relates to compounds of formula I that are useful as modulators of α7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer&#39;s disease, Parkinson&#39;s disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/345,997, filed Apr. 29, 2019, which is a National Phase applicationunder 35 U.S.C. § 371 of PCT Application No. PCT/US2017/058931, filedOct. 30, 2017, which published as WO2018/085170 on May 11, 2018, andclaims priority from U.S. Provisional Application Ser. No. 62/415,777,filed on Nov. 1, 2016 and U.S. Provisional Application Ser. No.62/558,602, filed on Sep. 14, 2017.

FIELD OF THE INVENTION

The present disclosure relates to compounds that are useful asmodulators of α7 nAChR, compositions comprising such compounds, and theuse of such compounds for preventing, treating, or ameliorating disease,particularly disorders of the central nervous system such as cognitiveimpairments in Alzheimer's disease, Parkinson's disease, andschizophrenia.

BACKGROUND OF THE INVENTION

The α7 nAChR is a fast desensitizing ligand-gated ion channel that hashigh permeability to Ca²⁺. In human brain, α7 nAChRs are highlyexpressed in the cortex and hippocampus, regions associated withcognition, see for example, Breese et al. J. Comp. Neurol. (1997)387:385-398. In neurons, α7 nAChRs are localized in both pre-synapticand post-synaptic structures, where activation of the receptor canmodulate neurotransmitter release, neuronal excitability, andintracellular signalling, see for example, Frazier et al. J. Neurosci.(1998) 18:1187-1195.

Cognitive impairments are prevalent in many neurological and psychiatricdiseases, including Alzheimer's disease (AD), schizophrenia, andParkinson's disease, and dysfunction in cholinergic signallingcontributes to the cognitive impairments of these diseases, see forexample, Francis et al. J. Neurol. Neurosurg. Psychiatry (1999)66:137-147. For example, a principal feature of the pathogenesis in ADis the loss of cholinergic neurons in the basal forebrain nuclei,whereas increasing cholinergic transmission via inhibition ofacetylcholine esterase is the standard of care for the cognitivesymptoms of AD. More specific to the α7 nAChR, it was recentlydemonstrated that encenicline, a partial agonist of the α7 nAChR,improves cognition in Alzheimer's disease, see for example, Moebius H etal., 67^(th) Annual Meeting Am. Acad. Neurol. (AAN) 2015, Abst P7.100.Evidence implicating α7 nAChRs in the etiology of schizophrenia comesfrom studies demonstrating reduced expression of neuronal α7 nAChRs inthe brain of schizophrenic patients and the observation thatschizophrenics frequently smoke, which is believed to be a form ofself-medication. In addition, variants in the promotor region of thegene coding for the α7 nAChR, CHRNA7, which impacts expression of the α7nAChR protein, are associated with symptoms of schizophrenia, see forexample, Sinkus el al. Neuropharmacology (2015) 96:274-288. Moreover,accumulating evidence from clinical trials has indicated that activatingα7 nAChR with agonists may have beneficial effects on cognition, see forexample, Keefe et al. Neuropsychopharmacology (2015) 40:3053-3060 andBertrand et al. Pharmacology Reviews (2015) 67:1025-1073. Therefore,targeting the α7 nAChR represents a therapeutic strategy for thetreatment of cognitive impairments associated with various cognitivedisorders.

Parkinson's disease (PD) is a neurodegenerative disease characterized byprogressive deficits in motor function, such as tremor, bradykinesia,rigidity and impaired postural reflex. The main pathological findingassociated with the disease is degeneration of dopaminergic neurons inthe Substantia nigra, resulting in loss of dopaminergic tone in thestriatum. L-DOPA is the current standard treatment for the motorsymptoms in PD. However, chronic treatment with L-DOPA in PD patientsalso induces dyskinesia, a side effect of L-DOPA therapy. New lines ofevidence indicate that activating al nAChRs acutely alleviatesdyskinesia in several animal models, see for example, Zhang et al. J.Pharmacol. Exp. Ther. (2014) 351:25-32. In addition, accumulatingevidence shows that pretreatment with al nAChR agonists may protectagainst neurodegeneration in nigrostriatal neurons, suggesting alactivation may have disease modifying properties too, see for example,Suzuki et al. J. Neurosci. Res. (2013) 91:462-471. Overall, al nAChR isan attractive target for both ameliorating disease progression andmanaging dyskinesia.

In addition to its expression in the central nervous system, the alnAChR is widely expressed in peripheral immune cells includingmacrophage, monocytes, dendritic cells, and B and T cells, see forexample, Rosas-Ballina et al. Science (2011) 334:98-101. Activation ofperipheral al nAChRs is critical for inhibiting the release ofproinflammatory cytokines via the cholinergic anti-inflammatory pathway,see for example, Wang et al. Nature (2003) 421:384-388. Therefore, alnAChR is a potential target for several inflammatory diseases such asrheumatoid arthritis, and atherosclerosis, see for example, W J de Jongeet al. British J. Pharmacol. (2007) 151:915-929.

In recent years, α7-selective positive allosteric modulators (PAMs) havebeen proposed as a therapeutic approach to treating cognitiveimpairments in AD, PD, and schizophrenia, as well as L-DOPAinduced-dyskinesia and inflammation. In contrast to al agonists thatactivate the channel irrespective of endogenous agonist, PAMs increasethe potency of the endogenous agonist without perturbing the temporaland spatial integrity of neurotransmission. There are two classs of α7PAMs, type I and type II, which differ based on the functionalproperties of modulation. The type I PAMs (e.g. NS1738, see for example,Timmermann et al. J. Pharmacol. Exp. Ther. (2007) 323:294-307)predominantly affect the peak current with little or no effect onreceptor desensitization, while the type II PAMs (e.g. PNU120596, seefor example, Hurst et al. J. Neurosci. (2005) 25:4396-4405) markedlydelay desensitization of the receptor. Additionally, α7 nAChR PAMs mayhave improved selectivity over related channel targets, presumablythrough binding to non-conserved regions of the receptor.

The present invention is directed to a new class of compounds thatexhibit positive allosteric modulation of the α7 nAChR.

SUMMARY OF THE INVENTION

The present disclosure relates to novel compounds of formula I andpharmaceutically acceptable salts thereof. These compounds may beuseful, either as compounds or their pharmaceutically acceptable salts(when appropriate), in the modulation of the α7 nAChR, the prevention,treatment, or amelioration of disease, particularly disorders of thecentral nervous system such as cognitive impairments in Alzheimer'sdisease, Parkinson's disease, and schizophrenia and/or as pharmaceuticalcomposition ingredients. As pharmaceutical composition ingredients,these compounds and their salts may be the primary active therapeuticagent, and, when appropriate, may be combined with other therapeuticagents including but not limited to acetylcholinesterase inhibitors,NMDA receptor antagonists, beta-secretase inhibitors, M4 mAChR agonistsor PAMs, mGluR2 antagonists or NAMs or PAMs, 5-HT6 antagonists,histamine H3 receptor antagonists, PDE4 inhibitors, PDE9 inhibitors,HDAC6 inhibitors, antipsychotics, MAO-B inhibitors, and levodopa.

In one aspect, the present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is selected from

-   -   Y is 4 substituents, each independently selected from H,        (C₁-C₄)alkyl, halogen, and OH, wherein said alkyl is optionally        substituted with one or more halogen or OH;    -   A is a 6-membered aryl or heteroaryl ring which is substituted        with 1 to 4 R groups each independently selected from OH, oxo,        amino, amido, carboxyl, keto, cyano, alkoxy, S(O)_(m)-alkyl,        halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, alkynyl,        aryl, heteroaryl, and heterocyclyl, wherein said amino, amido,        carboxyl, keto, alkoxy, S(O)_(m)-alkyl, aminoalkyl,        hydroxyalkyl, alkyl, cycloalkyl, alkynyl, aryl, heteroaryl and        heterocyclyl are optionally substituted with one or more        substituents independently selected from halogen, OH, oxo, CF₃,        OCF₃, CN, (C₁-C₆)alkyl, O(C₁-C₄)alkyl, S(O)_(m)—(C₁-C₄)alkyl,        C═O(C₁-C₄)alkyl, (C═O)NR⁷R⁸, (C═O)OR⁷, (C₂-C₄)alkynyl,        (C₃-C₆)cycloalkyl, O(C₃-C₆)cycloalkyl, C═O(C₃-C₆)cycloalkyl,        aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl,        heteroaryl and heterocyclyl are optionally independently        substituted with one or more halogen, CF₃, OH and oxo;    -   R¹ is H or (C₁-C₄)alkyl;    -   R² is H or (C₁-C₄)alkyl;    -   R³ is H, halogen, Si(CH₃)₃ or (C₁-C₄)alkyl, wherein said alkyl        is optionally substituted with one or more halogen;    -   R⁴ is H, halogen or (C₁-C₄)alkyl, wherein said alkyl is        optionally substituted with one or more halogen;    -   or, R³ and R⁴ optionally can come to together to form a        cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring wherein        said ring may be optionally substituted with one or more        substituents independently selected from OH, halogen, or        (C₁-C₄)alkyl;    -   R⁵ is H or (C₁-C₄)alkyl;    -   R⁶ is H or (C₁-C₄)alkyl;    -   R⁷ and R⁸ are independently selected from H, (C₁-C₆)alkyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said        alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are        optionally substituted with one or more substituents        independently selected from halogen, OH, CF₃, (C₁-C₄)alkyl,        O(C₁-C₄)alkyl, cycloalkyl, CN, aryl, heteroaryl, and        heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl are optionally substituted with one or more        substituents independently selected from halogen, OH, CF₃,        (C₁-C₄)alkyl, O(C₁-C₄)alkyl, CN;    -   R^(a) is H or (C₁-C₄)alkyl;    -   R^(b) is H or (C₁-C₄)alkyl; and    -   m is 0, 1, or 2.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of preventing, treating, or ameliorating the cognitiveimpairments associated with Alzheimer's disease, Parkinson's disease,and schizophrenia.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of formula I above, andpharmaceutically acceptable salts thereof. The compounds of formula Iare positive allosteric modulators of α7 nAChR.

In a first embodiment of the invention, X is

and the other groups are as provided in the general formula above.

In a second embodiment of the invention, Y is H and the other groups areas provided in the general formula above, or as in the first embodiment.

In a third embodiment of the invention, A is selected from pyridine,pyrimidine, phenyl, pyridazine, pyrazine, triazine, pyridinone,pyrimidinone, pyrazinone, and pyridazinone each substituted with 1 to 2R groups independently selected from halogen, CN, (C₁-C₆)alkyl,O(C₁-C₆)alkyl, NR⁷R⁸, (C₃-C₆)cycloalkyl, aryl, heteroaryl andheterocyclyl, wherein said alkyl, NR⁷R⁸, (C₃-C₆)cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents independently selected from halogen, CN, (C₁-C₄)alkyl,(C═O)O(C₁-C₄)alkyl and phenyl, wherein said alkyl is optionallysubstituted with one or more halogen; and the other groups are asprovided in the general formula above, or as in the first or secondembodiment.

In a fourth embodiment of the invention, R⁵, R⁶, R^(a) and R^(b) areindependently H or methyl, and the other groups are as provided in thegeneral formula above, or as in the first, second, or third embodiments.

In a fifth embodiment of the invention, R³ and R⁴ are independently H,F, Si(CH₃)₃ or methyl, and the other groups are as provided in thegeneral formula above, or as in the first through fourth embodiments.

In a sixth embodiment of the invention, R⁷ and R⁸ are independentlyselected from H, (C₁-C₆)alkyl, cyclopentyl and phenyl wherein said alkyland phenyl are optionally substituted with halogen or phenyl, and theother groups are as provided in the general formula above, or as in thefirst through fifth embodiments.

In a seventh embodiment of the invention, the compound of the inventionhas the formula:

or a pharmaceutically acceptable salt thereof, wherein;

-   -   A is selected from pyridine, pyrimidine, phenyl, pyridazine and        pyrazine each substituted with 1 R group selected from        (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸, (C₃-C₆)cycloalkyl, aryl,        heteroaryl and heterocyclyl, wherein each are optionally        substituted with one or more substituents independently selected        from halogen, CF₃, CN, (C₁-C₄)alkyl, (C═O)O(C₁-C₄)alkyl and        phenyl;    -   R³ is H or Si(CH₃)₃;    -   R⁴ is H; and    -   R⁷ and R⁸ are independently selected from H, (C₁-C₆)alkyl,        (C₃-C₆)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein        each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are        optionally substituted with one or more substituents        independently selected from halogen and phenyl.

In an eighth embodiment of the invention, the compound of the inventionhas the formula (Ia), or a pharmaceutically acceptable salt thereof,wherein;

-   -   A is selected from pyridine, pyrimidine, phenyl, pyridazine and        pyrazine each substituted with 1 R group selected from        (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸, cyclobutyl, cyclopentyl,        phenyl, pyridinyl, morpholinyl, imidazolyl, pyrazolyl,        oxadiazolyl, pyrrolidinyl, piperazinyl, triazolyl and        tetrahydropyranyl wherein each are optionally substituted with        one or more substituents independently selected from halogen,        CF₃, CN, (C₁-C₄)alkyl, (C═O)O(C₁-C₄)alkyl and phenyl;    -   R³ is H or Si(CH₃)₃;    -   R⁴ is H; and    -   R⁷ and R⁸ are independently selected from H, (C₁-C₆)alkyl,        cyclopentyl and phenyl, wherein each alkyl, cyclopentyl, and        phenyl are optionally substituted with one or more substituents        independently selected from halogen and phenyl.

The invention is also directed to a compound, or a pharmaceuticallyacceptable salt thereof, selected from the following exemplifiedcompounds:

-   4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[2-(Morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;-   4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;-   4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;-   4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(Pyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;-   4-[(1R,3R)-2,2-Dimethyl-3-{4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl]benzenesulfonamide;-   4-{trans-2-[4-(3-Fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;-   4-(trans-2-{4-[5-(Trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl)benzenesulfonamide;-   4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[4-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;-   4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[3-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(1H-Pyrazol-1-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[4-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;-   4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;-   4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;-   4-{2-[6-(Propan-2-yl)pyridin-3-yl]-3-(trimethylsilyl)cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(Propan-2-yl)pyridazin-3-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(Propan-2-yl)pyrazin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[5-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[5-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{(1R,3R)-2,2-Difluoro-3-[4-(3-fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[2-(Dimethylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[2-(Cyclopentylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[2-(Benzylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;-   tert-Butyl    4-{4-[trans-2-(4-sulfamoylphenyl)cyclopropyl]pyrimidin-2-yl}piperazine-1-carboxylate;-   4-(trans-2-{2-[(2,2-Dimethylpropyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;-   4-(trans-2-{2-[Methyl(phenyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;-   4-{trans-2-[2-(Pyrrolidin-1-yl)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;-   4-(trans-2-{2-[(4-Fluorophenyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;-   4-[trans-2-(2-Phenylpyrimidin-4-yl)cyclopropyl]benzenesulfonamide;-   4-(trans-2-{2-[(2-Phenylethyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;-   4-{trans-2-[2-(Phenylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;-   4-[trans-2-(2-Cyclobutylpyridin-4-yl)cyclopropyl]benzenesulfonamide;-   4-{trans-2-[4-(1H-Imidazol-1-yl)phenyl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[3-(1H-1,2,4-Triazol-1-yl)phenyl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(Propan-2-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[5-(Pyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(1H-Pyrazol-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;-   4-{trans-2-[6-(Propan-2-yloxy)pyridin-3-yl]cyclopropyl}benzenesulfonamide;    and-   4-{trans-2-[6-(2-Cyanopropan-2-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide.

Other embodiments of the present invention include the following:

-   -   (a) A pharmaceutical composition comprising a compound of        formula I and a pharmaceutically acceptable carrier.    -   (b) The pharmaceutical composition of (a), further comprising a        second therapeutic agent selected from the group consisting of        acetylcholinesterase inhibitors such as donepezil, rivastigmine,        and galantamine; NMDA receptor antagonists such as memantine;        beta-secretase inhibitors such as verubecestat, and AZD3293; M4        mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs;        5-HT6 antagonists such as idalopirdine, RVT-101, AVN-101,        AVN322, SUVN-502, and SYN-120; histamine H3 receptor antagonists        such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors        such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2        inhibitors; MAO-B inhibitors; and levodopa.    -   (c) The pharmaceutical composition of (b), wherein the second        therapeutic agent is an antipsychotic selected from the group        consisting of clozapine, olanzapine, risperidone, aripiprazole,        quetiapine, haloperidol, loxapine, thioridazine, molindone,        thiothixene, fluphenazine, mesoridazine, trifluoperazine,        chlorpromazine, and perphenazine.    -   (d) A pharmaceutical combination that is (i) a compound of        formula I and (ii) a second therapeutic agent selected from the        group consisting of acetylcholinesterase inhibitors such as        donepezil, rivastigmine, and galantamine; NMDA receptor        antagonists such as memantine; beta-secretase inhibitors such as        verubecestat, and AZD3293; M4 mAChR agonists or PAMs; mGluR2        antagonists or NAMs or PAMs; 5-HT6 antagonists such as        idalopirdine, RVT-101, AVN-101, AVN322, SUVN-502, and SYN-120;        histamine H3 receptor antagonists such as S38093; PDE4        inhibitors such as HT0712; PDE9 inhibitors such as BI40936;        HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B        inhibitors; and levodopa wherein the compound of formula I and        the second therapeutic agent are each employed in an amount that        renders the combination effective for treating cognitive        impairments associated with Alzheimer's disease, Parkinson's        disease, and schizophrenia.    -   (e) The combination of (d), wherein the second therapeutic agent        is an antipsychotic selected from the group consisting of        clozapine, olanzapine, risperidone, aripiprazole, quetiapine,        haloperidol, loxapine, thioridazine, molindone, thiothixene,        fluphenazine, mesoridazine, trifluoperazine, chlorpromazine, and        perphenazine.    -   (f) A use of a compound of formula I in the preparation of a        medicament for modulating α7 nAChR activity in a subject in need        thereof.    -   (g) A use of a compound of formula I in the preparation of a        medicament for treating cognitive impairments associated with        Alzheimer's disease, Parkinson's disease, and schizophrenia in a        subject in need thereof.    -   (h) A method of treating cognitive impairments associated with        Alzheimer's disease, Parkinson's disease, and schizophrenia        and/or reducing the likelihood or severity of symptoms of        cognitive impairments associated with Alzheimer's disease,        Parkinson's disease, and schizophrenia in a subject in need        thereof, which comprises administering to the subject an        effective amount of a compound of formula I.    -   (i) The method of (h), wherein the compound of formula I is        administered in combination with an effective amount of at least        one second therapeutic agent selected from the group consisting        of acetylcholinesterase inhibitors such as donepezil,        rivastigmine, and galantamine; NMDA receptor antagonists such as        memantine; beta-secretase inhibitors such as verubecestat, and        AZD3293; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs        or PAMs; 5-HT6 antagonists such as idalopirdine, RVT-101,        AVN-101, AVN322, SUVN-502, and SYN-120; histamine H3 receptor        antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9        inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics;        LRRK2 inhibitors; MAO-B inhibitors; and levodopa.    -   (j) The method of (i), wherein the second therapeutic agent is        an antipsychotic selected from the group consisting of        clozapine, olanzapine, risperidone, aripiprazole, quetiapine,        haloperidol, loxapine, thioridazine, molindone, thiothixene,        fluphenazine, mesoridazine, trifluoperazine, chlorpromazine, and        perphenazine.    -   (k) A method of modulating α7 nAChR activity in a subject in        need thereof, which comprises administering to the subject the        pharmaceutical composition of (a), (b), or (c) or the        combination of (d) or (e).    -   (l) A method of treating cognitive impairments associated with        Alzheimer's disease, Parkinson's disease, and schizophrenia        and/or reducing the likelihood or severity of symptoms of        cognitive impairments associated with Alzheimer's disease,        Parkinson's disease, and schizophrenia in a subject in need        thereof, which comprises administering to the subject the        pharmaceutical composition of (a), (b), or (c) or the        combination of (d) or (e).

In the embodiments of the compounds and salts provided above, it is tobe understood that each embodiment may be combined with one or moreother embodiments, to the extent that such a combination provides astable compound or salt and is consistent with the description of theembodiments. It is further to be understood that the embodiments ofcompositions and methods provided as (a) through (l) above areunderstood to include all embodiments of the compounds and/or salts,including such embodiments as result from combinations of embodiments.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations, uses and methods set forth in (a) through(l) above, wherein the compound of the present invention employedtherein is a compound of one of the embodiments, aspects, classes,sub-classes, or features of the compounds described above. In all ofthese embodiments, the compound may optionally be used in the form of apharmaceutically acceptable salt or hydrate as appropriate.

The present invention also includes a compound of the present inventionfor use (i) in, (ii) as a medicament for, or (iii) in the preparation ofa medicament for: (a) preventing or treating cognitive impairmentsassociated with Alzheimer's disease, Parkinson's disease, schizophrenia,and L-DOPA induced-dyskinesia, or (b) treating cognitive impairmentsassociated with Alzheimer's disease, Parkinson's disease, schizophrenia,and L-DOPA induced-dyskinesia and/or reducing the likelihood or severityof symptoms of cognitive impairments associated with Alzheimer'sdisease, Parkinson's disease, schizophrenia, and L-DOPAinduced-dyskinesia, or (c) use in medicine. In these uses, the compoundsof the present invention can optionally be employed in combination withone or more second therapeutic agents selected from acetylcholinesteraseinhibitors such as donepezil, rivastigmine, and galantamine; NMDAreceptor antagonists such as memantine; beta-secretase inhibitors suchas verubecestat, and AZD3293; M4 mAChR agonists or PAMs; mGluR2antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopirdine,RVT-101, AVN-101, AVN322, SUVN-502, and SYN-120; histamine H3 receptorantagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2inhibitors; MAO-B inhibitors; and levodopa.

Chemical names, common names, and chemical structures may be usedinterchangeably to describe the same structure.

As used herein, the term “6-membered aryl or heteroaryl ring” refers toa stable unsaturated 6-membered ring that contains from 0 to 4heteroatoms selected from the group consisting of O, N, and S. A6-membered aryl or heteroaryl ring within the scope of this definitionincludes but is not limited to: pyridine, pyrimidine, phenyl, pyridazineand pyrazine.

As used herein, the term “administration” and variants thereof (e.g.,“administering” a compound) in reference to a compound of the inventionmeans providing the compound to the individual in need of treatment.When a compound of the invention is provided in combination with one ormore other active agents (e.g., cholinesterase inhibitors such asdonepezil, rivastigmine, and galantamine), “administration” and itsvariants are each understood to include concurrent and sequentialprovision of the compound or salt and other agents.

The term “alkoxy” refers to an “alkyl-O—” group. Alkoxy groups may besubstituted as indicated.

The term “alkyl” refers to an aliphatic hydrocarbon group having one ofits hydrogen atoms replaced with a bond. An alkyl group may be straightor branched and contain from 1 to 12 carbon atoms. In differentembodiments, an alkyl group contains from 1 to 6 carbon atoms[(C₁-C₆)alkyl] or from 1 to 4 carbon atoms [(C₁-C₄)alkyl] or from 1 to 3carbon atoms [(C₁-C₃)alkyl], Non-limiting examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyland neohexyl. In one embodiment, an alkyl group is linear. In anotherembodiment, an alkyl group is branched.

The term “alkynyl” refers to a hydrocarbon radical straight or branchedcontaining from 2 to 12 carbon atoms and at least one carbon to carbontriple bond. Up to three carbon-carbon triple bonds may be present.Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to 6 carbonatoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. In one embodiment, an alkynyl group islinear. In another embodiment, an alkynyl group is branched.

The term “aryl” (or “aryl ring system”) refers to any mono- andpoly-carbocyclic ring systems wherein the individual carbocyclic ringsin the polyring systems are fused or attached to each other via a singlebond and wherein at least one ring is aromatic. Suitable aryl groupsinclude phenyl, indanyl, naphthyl, tetrahydronaphthyl, and biphenyl.Aryl ring systems may include, where appropriate, an indication of thevariable to which a particular ring atom is attached. Unless otherwiseindicated, substituents to the aryl ring systems can be attached to anyring atom, provided that such attachment results in formation of astable ring system.

The term “composition” is intended to encompass a product comprising thespecified ingredients, as well as any product which results fromcombining the specified ingredients.

The term “compound” is intended to encompass chemical agents describedby generic formula I in all forms. Such chemical agents can be presentin different forms such as hydrates, solvates, and polymorphs.

The term “cycloalkyl” as used herein, refers to anon-aromatic mono- ormulti cyclic ring system comprising from 3 to 10 ring carbon atoms. Inone embodiment, a cycloalkyl contains from 5 to 10 ring carbon atoms. Inanother embodiment, a cycloalkyl contains from 3 to 7 ring atoms. Inanother embodiment, a cycloalkyl contains from 3 to 6 ring atoms[(C₃-C₆)cycloalkyl], In another embodiment, a cycloalkyl contains from 5to 7 ring atoms. In another embodiment, a cycloalkyl contains from 5 to6 ring atoms. The term “cycloalkyl” also encompasses a cycloalkyl group,as defined above, which is fused to an aryl (e.g., benzene) orheteroaryl ring. Non-limiting examples of monocyclic cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Non-limiting examples of multi cyclic cycloalkyls include1-decalinyl, norbornyl, bicyclo[3.1.0]hexyl and adamantyl. The term “3to 7-membered cycloalkyl” refers to a cycloalkyl group having from 3 to7 ring carbon atoms. A ring carbon atom of a cycloalkyl group may befunctionalized as a carbonyl group. An illustrative example of such acycloalkyl group (also referred to herein as a “cycloalkanoyl” group)includes, but is not limited to, cyclobutanoyl:

The term “effective amount” as used herein means that amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.In one embodiment, the effective amount is a “therapeutically effectiveamount” for the alleviation of one or more symptoms of the disease orcondition being treated. In another embodiment, the effective amount isa “prophylactically effective amount” for reduction of the severity orlikelihood of one or more symptoms of the disease or condition. The termalso includes herein the amount of active compound sufficient tomodulate α7 nAChR activity and thereby elicit the response being sought(i.e., a “therapeutically effective amount”). When the active compound(i.e., active ingredient) is administered as the salt, references to theamount of active ingredient are to the free acid or free base form ofthe compound.

The term “halogen” (or “halo”) refers to atoms of fluorine, chlorine,bromine and iodine (alternatively referred to as fluoro, chloro, bromo,and iodo).

The term “heteroaryl” as used herein, refers to any monocyclic ormulticyclic ring system comprising 5 to 14 ring atoms, wherein from 1 to4 of the ring atoms is independently O, N, or S and the remaining ringatoms are carbon atoms, and wherein at least one ring is aromatic. Inone embodiment, a heteroaryl group has 5 to 10 ring atoms. In anotherembodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms.In another embodiment, a heteroaryl group is bicyclic and has 9 or 10ring atoms. A heteroaryl group is usually joined via a ring carbon atombut may be joined via a non-carbon atom provided that this results in astable compound, and any nitrogen atom of a heteroaryl can be optionallyoxidized to the corresponding N-oxide. The term “heteroaryl” alsoencompasses a heteroaryl group, as defined above, which is fused to abenzene ring. The term “heteroaryl” also encompasses any fusedpolycyclic ring system containing at least one ring heteroatom selectedfrom N, O, and S, wherein at least one ring of the fused polycyclic ringsystem is aromatic. For example, the term “9 to 10-membered bicyclicheteroaryl” encompasses anon-aromatic 5 membered heterocyclic ring thatis fused to a benzene or pyridyl ring. Non-limiting examples ofheteroaryls include benzimidazolyl, benzimidazolonyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl,thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl,dihydroquinolinyl, methylenedioxybenzoyl and the like, and all isomericforms thereof. The term “heteroaryl” also refers to partially saturatedheteroaryl moieties such as, for example, tetrahydroisoquinolyl,tetrahydroquinolyl and the like, provided that they contain at least onearomatic ring. In one embodiment, a heteroaryl group is a 5-memberedheteroaryl. In another embodiment, a heteroaryl group is a 6-memberedheteroaryl. In another embodiment, a heteroaryl group comprises a 5- to6-membered heteroaryl group fused to a benzene ring.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3- to 10-membered non-aromatic heterocycle containing from 1 to 4heteroatoms selected from the group consisting of O, N, and S, andincludes monocyclic or bicyclic groups (fused, bridged or spirocyclic).Further examples of “heterocyclyl” include, but are not limited to thefollowing: oxazoline, isoxazoline, oxetanyl, tetrahydropyranyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl,dihydroimidazolyl, dihydroisooxazolyl, dihydroisothiazolyl,dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, tetrahydrofuranyl, andtetrahydrothienyl, and N-oxides thereof. Attachment of a heterocyclylsubstituent can occur via a carbon atom or via a heteroatom.

The term “hydroxyalkyl” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with an —OH group. In one embodiment, a hydroxyalkylgroup has from 1 to 6 carbon atoms. Non-limiting examples ofhydroxyalkyl groups include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH and—CH₂CH(OH)CH₃. The term “C₁-C₆ hydroxyalkyl” refers to a hydroxyalkylgroup having from 1 to 6 carbon atoms. The term “C₁-C₄ hydroxyalkyl”refers to a hydroxyalkyl group having from 1 to 4 carbon atoms. The term“C₁-C₃ hydroxyalkyl” refers to a hydroxyalkyl group having from 1 to 3carbon atoms.

As used herein, the term “oxo” or “═O” forms a carbonyl moiety with thecarbon atom to which it is attached.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “preventing” as used herein with respect to Alzheimer's diseaseor other neurological diseases, refers to reducing the likelihood ofdisease progression.

The term “subject” (alternatively referred to herein as “patient”), asused herein, refers to an animal, preferably a mammal, most preferably ahuman.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Unless expressly stated to the contrary, substitutionby a named substituent is permitted on any atom provided suchsubstitution is chemically allowed and results in a stable compound.Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. A “stable” compound is acompound that can be prepared and isolated and whose structure andproperties remain or can be caused to remain essentially unchanged for aperiod of time sufficient to allow use of the compound for the purposesdescribed herein (e.g., therapeutic or prophylactic administration to asubject).

In another embodiment of formula I, X is selected from

wherein R¹, R², and R^(b) is H.

In another embodiment of formula I, X is

wherein R¹ and R² are H.

In another embodiment of formula I, Y is 4 substituents, eachindependently selected from H, (C₁-C₄)alkyl, halogen, and OH, whereinsaid alkyl is optionally substituted with one or more halogen or OH.

In another embodiment of formula I, Y is H.

In another embodiment of formula I, A is a 6-membered aryl or heteroarylring which is substituted with 1 to 3 R groups independently selectedfrom OH, oxo, halogen, CN, (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸,(C₃-C₆)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each areoptionally substituted with one or more substituents independentlyselected from halogen, CN, (C₁-C₄)alkyl. (C═O)O(C₁-C₄)alkyl and phenyl.

In another embodiment of formula I, A is a 6-membered aryl or heteroarylring which is substituted with 1 to 2 R groups independently selectedfrom OH, oxo, halogen, CN, (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸,(C₃-C₆)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each areoptionally substituted with one or more substituents independentlyselected from halogen, CN, (C₁-C₄)alkyl, (C═O)O(C₁-C₄)alkyl and phenyl.

In another embodiment of formula I, A is selected from pyridine,pyrimidine, phenyl, pyridazine, pyrazine, triazine, pyridinone,pyrimidinone, pyrazinone, and pyridazinone each substituted with 1 to 3R groups independently selected from (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸,(C₃-C₆)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each areoptionally substituted with one or more substituents independentlyselected from halogen, CN, (C₁-C₄)alkyl, (C═O)O(C₁-C₄)alkyl and phenyl.

In another embodiment of formula I, A is selected from pyridine,pyrimidine, phenyl, pyridazine and pyrazine each substituted with 1 to 2R groups independently selected from (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸,(C₃-C₆)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each areoptionally substituted with one or more substituents independentlyselected from halogen, CN, (C₁-C₄)alkyl, (C═O)O(C₁-C₄)alkyl and phenyl.

In another embodiment of formula I, A is selected from pyridine,pyrimidine, phenyl, pyridazine and pyrazine each substituted with 1 to 3R groups independently selected from (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸,cyclobutyl, cyclopentyl, phenyl, morpholinyl, imidazolyl, pyrazolyl,oxadiazolyl, pyrrolidinyl, triazolyl and tetrahydropyranyl wherein eachare optionally substituted with one or more substituents independentlyselected from halogen, CN, (C₁-C₄)alkyl, (C═O)O(C₁-C₄)alkyl and phenyl.

In another embodiment of formula I, A is selected from pyridine,pyrimidine, phenyl, pyridazine and pyrazine each substituted with 1 to 2R groups independently selected from (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸,cyclobutyl, cyclopentyl, phenyl, morpholinyl, imidazolyl, pyrazolyl,oxadiazolyl, pyrrolidinyl, triazolyl and tetrahydropyranyl wherein eachare optionally substituted with one or more substituents independentlyselected from halogen, CN, (C₁-C₄)alkyl, (C═O)O(C₁-C₄)alkyl and phenyl.

In another embodiment of formula I, R¹ is H or methyl.

In another embodiment of formula I, R² is H or methyl.

In another embodiment of formula I or Ia, R³ is H or Si(CH₃)₃.

In another embodiment of formula I or Ia, R⁴ is H.

In another embodiment of formula I, R³ and R⁴ optionally can come totogether to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylring wherein said ring may be optionally substituted with one or moresubstituents independently selected from OH, halogen, or (C₁-C₄)alkyl.

In another embodiment of formula I, R³ and R⁴ optionally can come totogether to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylring.

In another embodiment of formula I, R⁵ is H or methyl.

In another embodiment of formula I, R⁶ is H or methyl.

In another embodiment of formula I, R^(a) is H or methyl.

In another embodiment of formula I, R^(b) is H or methyl.

In another embodiment of formula I, R⁵ is H.

In another embodiment of formula I, R⁶ is H.

In another embodiment of formula I or Ia, R⁷ and R⁸ are independentlyselected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl and phenyl.

In another embodiment of formula I or Ia, R⁷ and R⁸ are independentlyselected from H, (C₁-C₆)alkyl, cyclopentyl and phenyl.

In another embodiment of formula I, R^(a) is H.

In another embodiment of formula I, R^(b) is H.

In the compounds of formula I, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of formula I. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H or D). Protium is the predominant hydrogen isotopefound in nature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin formula I can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heteroaryl ring described as containing from“1 to 3 heteroatoms” means the ring can contain 1, 2, or 3 heteroatoms.It is also to be understood that any range cited herein includes withinits scope all of the sub-ranges within that range. The oxidized forms ofthe heteroatoms N and S are also included within the scope of thepresent invention.

It is understood by one skilled in the art that carbon atoms in organicmolecules may often be replaced by silicon atoms to give analogousstable compounds. For example, carbon atoms in alkoxy, alkyl,cycloalkyl, heteroaryl, heterocyclyl, and hydroxyalkyl groups may oftenbe replaced by silicon atoms to provide stable compounds. All suchcompounds are within the scope of the present invention.

When any variable (for example, R) occurs more than one time in anyconstituent or in formula I or in any other formula depicting anddescribing compounds of the invention, its definition on each occurrenceis independent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Certain of the compounds of the present invention can have asymmetriccenters and can occur as mixtures of stereoisomers, or as individualdiastereomers, or enantiomers. All isomeric forms of these compounds,whether isolated or in mixtures, are within the scope of the presentinvention.

Certain of the compounds of the present invention can exist astautomers. For the purposes of the present invention a reference to acompound of formula I is a reference to the compound per se, or to anyone of its tautomers per se, or to mixtures of two or more tautomers.

The compounds of the present invention may have utility in preventing,treating, or ameliorating Alzheimer's disease. The compounds may also beuseful in preventing, treating, or ameliorating other diseases mediatedby the α7 nAChR, such as schizophrenia, sleep disorders, Parkinson'sdisease, autism, microdeletion syndrome, inflammatory diseases, paindisorders (including acute pain, inflammatory pain and neuropathic pain)and cognitive disorders (including mild cognitive impairment). Otherconditions that may be prevented, treated, or ameliorated by thecompounds of the invention include pulmonary hypertension, chronicobstructive pulmonary disease (COPD), asthma, urinary incontinence,glaucoma, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy,degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosisof the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders,amyotrophic lateral sclerosis, progressive supranuclear palsy, headtrauma, stroke, pancreatitis, inclusion body myositis, other peripheralamyloidoses, diabetes, kidney diseases, cancer, and atherosclerosis.

In preferred embodiments, the compounds of the invention may be usefulin preventing, treating, or ameliorating Alzheimer's Disease, cognitivedisorders, schizophrenia, pain disorders and sleep disorders. Forexample, the compounds may be useful for the prevention of dementia ofthe Alzheimer's type, as well as for the treatment of early stage,intermediate stage or late stage dementia of the Alzheimer's type.

Potential schizophrenia conditions or disorders for which the compoundsof the invention may be useful include one or more of the followingconditions or diseases: schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketamine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illness associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome), including both the positiveand the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orage related cognitive decline.

Thus, in another specific embodiment, the present invention provides amethod for preventing, treating, or ameliorating schizophrenia orpsychosis comprising administering to a patient in need thereof aneffective amount of a compound of the present invention. At present, thetext revision of the fourth edition of the Diagnostic and StatisticalManual of Mental Disorders (DSM-IV-TR) (2000, American PsychiatricAssociation, Washington D.C.) provides a diagnostic tool that includesparanoid, disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. As used herein, the term“schizophrenia or psychosis” includes treatment of those mentaldisorders as described in DSM-IV-TR. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies and classificationsystems for mental disorders, and that these systems evolve with medicaland scientific progress. Thus the term “schizophrenia or psychosis” isintended to include like disorders that are described in otherdiagnostic sources.

Potential sleep conditions or disorders for which the compounds of theinvention may be useful include enhancing sleep quality; improving sleepquality; augmenting sleep maintenance; increasing the value which iscalculated from the time that a subject sleeps divided by the time thata subject is attempting to sleep; decreasing sleep latency or onset (thetime it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleepapnea; wakefulness; nocturnal myoclonus; REM sleep interruptions;jet-lag; shift workers' sleep disturbances; dyssomnias; night terror;insomnias associated with depression; emotional/mood disorders; as wellas sleep walking and enuresis; and sleep disorders which accompanyaging; Alzheimer's sundowning; conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules;conditions due to drugs which cause reductions in REM sleep as a sideeffect; syndromes which are manifested by non-restorative sleep andmuscle pain or sleep apnea which is associated with respiratorydisturbances during sleep; and conditions which result from a diminishedquality of sleep.

Pain disorders for which the compounds of the invention may be usefulinclude neuropathic pain (such as postherpetic neuralgia, nerve injury,the “dynias”, e.g., vulvodynia, phantom limb pain, root avulsions,painful diabetic neuropathy, painful traumatic mononeuropathy, painfulpolyneuropathy); central pain syndromes (potentially caused by virtuallyany lesion at any level of the nervous system); postsurgical painsyndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stumppain); bone and joint pain (osteoarthritis); repetitive motion pain;dental pain; cancer pain; myofascial pain (muscular injury,fibromyalgia); perioperative pain (general surgery, gynecological);chronic pain; dysmennorhea, as well as pain associated with angina, andinflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout); headache;migraine and cluster headache; primary hyperalgesia; secondaryhyperalgesia; primary allodynia; secondary allodynia; or other paincaused by central sensitization.

Potential conditions or disorders that have a strong inflammatorycomponent for which the compounds of the invention may be useful includeone or more of the following conditions or diseases: diabetes (systemicinflammation in diabetes marked by increases in blood cytokines e.g.IL-6 and TNFα which may lead to insulin resistance); asthma; arthritis;cystic fibrosis; sepsis; ulcerative colitis; inflammatory bowel disease;atherosclerosis; neuroinflammation associated with neurodegenerativediseases (e.g. Alzheimer's disease, Parkinson's disease,Creutzfeldt-Jacob disease, frontotemporal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy, traumaticbrain injury, Huntington's disease, amyotrophic lateral sclerosis).

Compounds of the invention may also be used to treat or prevent orameliorate dyskinesia and protect against neurodegeneration innigrostriatal neurons in Parkinson's disease. Furthermore, compounds ofthe invention may be used to decrease tolerance and/or dependence toopioid treatment of pain, and for treatment of withdrawal syndrome ofe.g., alcohol, opioids, and cocaine.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt that possesses the effectiveness ofthe parent compound and that is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts that may,for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. Many of the compounds of the invention carry anacidic moiety, in which case suitable pharmaceutically acceptable saltsthereof can include alkali metal salts (e.g., sodium or potassiumsalts), alkaline earth metal salts (e.g., calcium or magnesium salts),and salts formed with suitable organic ligands such as quaternaryammonium salts. Also, in the case of an acid (—COOH) or alcohol groupbeing present, pharmaceutically acceptable esters can be employed tomodify the solubility or hydrolysis characteristics of the compound.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates(“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates,propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1): 1-19; P. Gould, International J. of Pharmaceutics(1986) 33:201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website).

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, t-butyl amine, choline, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

For the purposes of preventing, treating, or ameliorating the cognitiveimpairments in Alzheimer's disease, Parkinson's disease, schizophrenia,L-DOPA induced-dyskinesia, and inflammation, the compounds of thepresent invention, optionally in the form of a salt, can be administeredby any means that produces contact of the active agent with the agent'ssite of action. They can be administered by one or more conventionalmeans available for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.They can be administered alone, but typically are administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice. The compounds ofthe invention can, for example, be administered by one or more of thefollowing: orally, parenterally (including subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques), by inhalation (such as in a spray form), or rectally, inthe form of a unit dosage of a pharmaceutical composition containing aneffective amount of the compound and conventional non-toxicpharmaceutically-acceptable carriers, adjuvants and vehicles. Liquidpreparations suitable for oral administration (e.g., suspensions,syrups, elixirs and the like) can be prepared according to techniquesknown in the art and can employ any of the usual media such as water,glycols, oils, alcohols and the like. Solid preparations suitable fororal administration (e.g., powders, pills, capsules and tablets) can beprepared according to techniques known in the art and can employ suchsolid excipients as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like. Parenteral compositions can beprepared according to techniques known in the art and typically employsterile water as a carrier and optionally other ingredients, such assolubility aids. Injectable solutions can be prepared according tomethods known in the art wherein the carrier comprises a salinesolution, a glucose solution or a solution containing a mixture ofsaline and glucose. Further description of methods suitable for use inpreparing pharmaceutical compositions of the present invention and ofingredients suitable for use in said compositions is provided inRemington's Pharmaceutical Sciences, 18^(th) edition (ed. A. R. Gennaro,Mack Publishing Co., 1990).

The compounds of this invention can be administered orally in a dosagerange of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per dayin a single dose or in divided doses. One dosage range is 0.01 to 500mg/kg body weight per day orally in a single dose or in divided doses.Another dosage range is 0.1 to 100 mg/kg body weight per day orally insingle or divided doses. For oral administration, the compositions canbe provided in the form of tablets or capsules containing 1.0 to 500 mgof the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75,100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient forthe symptomatic adjustment of the dosage to the patient to be treated.The specific dose level and frequency of dosage for any particularpatient may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, and the severity of the particularcondition.

As noted above, the present invention also relates to a method ofpreventing, treating, or ameliorating the cognitive impairments inAlzheimer's disease, Parkinson's disease, schizophrenia, L-DOPAinduced-dyskinesia, and inflammation with a compound of the presentinvention in combination with one or more therapeutic agents and apharmaceutical composition comprising a compound of the presentinvention and one or more therapeutic agents selected from the groupconsisting of anti-Alzheimer's Disease agents, for examplebeta-secretase inhibitors such as verubecestat; Ml mAChR agonist orPAMs; M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs;ADAM 10 ligands or activators; gamma-secretase inhibitors, such asLY450139 and TAK 070; gamma secretase modulators; tau phosphorylationinhibitors; glycine transport inhibitors; LXR β agonists; ApoE4conformational modulators; NR2B antagonists; androgen receptormodulators; blockers of Aβ oligomer formation; 5-HT4 agonists, such asPRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518, FK-962,SL-65.0155, SRA-333 and xaliproden; 5-HT1a antagonists, such aslecozotan; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2inhibitors; LRRK2 inhibitors; HMG-CoA reductase inhibitors; NSAIDsincluding ibuprofen; vitamin E; anti-amyloid antibodies (includinganti-amyloid humanized monoclonal antibodies), such as bapineuzumab,ACC001, CAD106, AZD3102, H12A11V1; anti-inflammatory compounds such as(R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, FIT-0712 andEHT-202; PPAR gamma agonists, such as pioglitazone and rosiglitazone;CB-1 receptor antagonists or CB-1 receptor inverse agonists, such asAVE1625; antibiotics such as doxycycline and rifampin;N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine,neramexane and EVT101; cholinesterase inhibitors such as galantamine,rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089;growth hormone secretagogues such as ibutamoren, ibutamoren mesylate,and capromorelin; histamine H3 receptor antagonists such as ABT-834, ABT829, GSK 189254 and CEP16795; AMPA agonists or AMPA modulators, such asCX-717, LY 451395, LY404187 and S-18986; PDE IV inhibitors, includingMEM1414, HT0712 and AVE8112; GABAA inverse agonists; GSK3β inhibitors,including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists;selective M1 agonists; HDAC inhibitors; and microtubule affinityregulating kinase (MARK) ligands; or other drugs that affect receptorsor enzymes that either increase the efficacy, safety, convenience, orreduce unwanted side effects or toxicity of the compounds of the presentinvention.

Examples of combinations of the compounds of the instant inventioninclude combinations with agents for the treatment of schizophrenia, forexample in combination with sedatives, hypnotics, anxiolytics,antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,aiprazolam, amisulpride, amitriptyline, amobarbital, amoxapine,aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capuride, carbocloral, chloralbetaine, chloral hydrate, clomipramine, clonazepam, cloperidone,clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine,cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone,divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol,etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine,flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam,maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam,nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine,pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital,prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine,reclazepam, risperidone, roletamide, secobarbital, sertraline,suproelone, temazepam, thioridazine, thiothixene, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and saltsthereof, and combinations thereof, and the like, or the subject compoundmay be administered in conjunction with the use of physical methods suchas with light therapy or electrical stimulation.

In another embodiment, the compounds of the instant invention may beemployed in combination with levodopa (with or without a selectiveextracerebral decarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride; COMTinhibitors such as entacapone, MAO-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

In another embodiment, the compound of the instant invention may beemployed in combination with a compound from the phenothiazine,thioxanthene, heterocyclic dibenzazepine, butyrophenone,diphenylbutylpiperidine and indolone classes of neuroleptic agent.Suitable examples of phenothiazines include chlorpromazine,mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazineand trifluoperazine. Suitable examples of thioxanthenes includechlorprothixene and thiothixene. An example of a dibenzazepine isclozapine. An example of a butyrophenone is haloperidol. An example of adiphenylbutylpiperidine is pimozide. An example of an indolone ismolindolone. Other neuroleptic agents include loxapine, sulpiride andrisperidone. It will be appreciated that the neuroleptic agents whenused in combination with the compounds of the instant invention may bein the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the compounds of the instantinvention may be employed in combination with acetophenazine, alentemol,aripiprazole, amisuipride, benzhexol, bromocriptine, biperiden,chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam,fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopawith carbidopa, lisuride, loxapine, mesoridazine, molindolone,naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole,quetiapine, risperidone, sulpiride, tetrabenazine, frihexyphenidyl,thioridazine, thiothixene, trifluoperazine or ziprasidone.

Examples of combinations of the compounds of the instant inventioninclude combinations with agents for the treatment of pain, for examplenon-steroidal anti-inflammatory agents, such as aspirin, diclofenac,duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac andtolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib,406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-1antagonists, such as AMG517, 705498, 782443, PAC20030, V114380 andA425619; bradykinin B1 receptor antagonists, such as SSR240612 andNVPSAA164; sodium channel blockers and antagonists, such as VX409 andSPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOSinhibitors), such as SD6010 and 274150; glycine site antagonists,including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDAantagonists, such as AZD4282; potassium channel openers; AMPA/kainatereceptor antagonists; calcium channel blockers, such as ziconotide andNMED160; GABA-A receptor IO modulators (e.g., a GABA-A receptoragonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents;opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol,meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine,propoxyphene; neutrophil inhibitory factor (NIF); pramipexole,ropinirole; anticholinergics; amantadine; monoamine oxidase B15(“MAO-B”) inhibitors; 5HT receptor agonists or antagonists; mGlu5antagonists, such as AZD9272; alpha agonists, such as AGN XX/YY;neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists orantagonists, such as AZD4282; NKI antagonists; selective serotoninreuptake inhibitors (“SSRI”) and/or selective serotonin andnorepinephrine reuptake inhibitors (“SSNRI”), such as duloxetine;tricyclic antidepressant drugs, norepinephrine modulators; lithium;valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan;naratriptan and sumatriptan.

The compounds of the present invention may be administered incombination with compounds useful for enhancing sleep quality andpreventing and treating sleep disorders and sleep disturbances,including e.g., sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, antihistamines, benzodiazepines, barbiturates,cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists,5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2Cantagonists, histamine antagonists including histamine H3 antagonists,histamine H3 inverse agonists, imidazopyridines, minor tranquilizers,melatonin agonists and antagonists, melatonergic agents, other orexinantagonists, orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde,paroxetine, pentobarbital, perlapine, perphenazine, phenelzine,phenobarbital, prazepam, promethazine, propofol, protriptyline,quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline,suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and saltsthereof, and combinations thereof, and the like, or the compound of thepresent invention may be administered in conjunction with the use ofphysical methods such as with light therapy or electrical stimulation.

Compounds of the instant invention are useful for the treatment ofmoderate to severe dementia of the Alzheimer's type alone or incombination with an NMDA receptor antagonist, such as memantine, or incombination with an acetylcholinesterase inhibitor (AChEI) such asdonepezil.

Compounds of the instant invention are useful for the treatment of mildto moderate dementia of the Alzheimer's type alone or in combinationwith either galantamine, rivastigmine, or donepezil.

Compounds of the instant invention are useful for the treatment ofdementia associated with Parkinson's disease alone or in combinationwith rivastigmine.

Compounds of the instant invention are useful for the treatment of motorfluctuations in patients with advanced Parkinson's disease alone or incombination with carbidopa and levodopa.

When administering a combination therapy of the invention to a patient,therapeutic agents in the combination, or a pharmaceutical compositionor compositions comprising therapeutic agents, may be administered inany order such as, for example, sequentially, concurrently, together,simultaneously and the like. The amounts of the various actives in suchcombination therapy may be different amounts (different dosage amounts)or same amounts (same dosage amounts). A compound of the invention andan additional therapeutic agent may be present in fixed amounts (dosageamounts) in a single dosage unit (e.g., a capsule, a tablet and thelike).

The α7 nAChR positive allosteric modulator (PAM) activity of the presentcompounds may be tested using assays known in the art. The α7 nAChR PAMsdescribed herein have activities in an automated patch-clampelectrophysiology functional assay as described in the examples. Theassay was performed using the IonFlux HT in a whole-cell, populationpatch configuration. See Golden et al. Assay Drug Dev. Technol. (2011)9:608-619. The compounds were assessed for their ability to modulate thefunction of the human α7 nAChR stably expressed in a HEK cell line bothin the presence, and in the absence of the natural α7 agonistacetylcholine. By performing a series of such measurements at differentconcentrations, the effective concentration of the α7 nAChR PAMs (EC₅₀)was determined. See Spencer et al. Assay Drug Dev Technol. (2012)10:313-324.

General Schemes

The compounds of the present invention can be prepared readily accordingto the following schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthetic procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following schemes.

Many compounds of the present invention may be prepared according toScheme 1, in which boronic acid 1.1 is reacted with bromide 1.2, whichcould be aryl or heteroaryl, under palladium-catalyzed conditions toafford product 1.3. Similar chemistry may be performed using a boronateester or boronic acid derivative in place of the boronic acid and achloride, iodide, triflate, or tosylate, for example, as alternatives tobromide. A variety of different catalysts, which includes other metalssuch as nickel, ligands, bases, and solvents can be employed in thisreaction. Compound 1.3 is then sulfonylated by treatment with neatchlorosulfonic acid followed by treatment of the resultant sulfonylchloride with a solution of ammonia in a solvent, such as water,1,4-dioxane, tetrahydrofuran, or methanol, to afford sulfonamide product1.4. Similar chemistry may be carried out employing a mixture of ahalogenated solvent and chlorosulfonic acid as opposed to the neat acid.If 1.4 is a mixture of enantiomers or diastereomers, the mixture may beseparated by chiral chromatography. Alternatively, 1.1 and 1.2 may beemployed as single enantiomers or diastereomers to obtain 1.4 enrichedin a single enantiomer or diastereomer.

Specific compounds of the present invention may be prepared using thisgeneral method as described in Scheme 2, in which(2-phenylcyclopropyl)boronic acid (2.1) is reacted with 2-bromopyridine2.2 under palladium-catalyzed conditions to afford product 2.3. Avariety of different catalysts, which includes other metals such asnickel, ligands, bases, and solvents can be employed in this reaction.Pyridine 2.3 is then sulfonylated by treatment with chlorosulfonic acidand the resultant sulfonyl chloride reacted with aqueous ammoniumhydroxide to afford racemic sulfonamide product 2.4. Racemic sulfonamide2.4 can then be separated by chiral chromatography to afford theindividual enantiomers.

In addition, compounds in the present invention may be preparedaccording to Scheme 3, in which α,β-unsaturated ketone 3.1 is reactedwith amidine 3.2 in the presence of potassium carbonate at elevatedtemperature to afford product 3.3. Other bases and solvents can beemployed in this transformation. Additionally, if removal of theformamidine group from the sulfonamide is incomplete, the product of thereaction can be treated with hydrazine hydrate to complete thedeprotection.

In addition, compounds in the present invention may be preparedaccording to Scheme 4, in which boronate ester 4.1 is reacted withheteroaryl 4.2 under palladium-catalyzed conditions followed bytreatment with hydrazine hydrate to afford product 4.3. Similarchemistry may be performed using a boronate ester or boronic acidderivative in place of the boronic acid and a chloride, iodide,triflate, or tosylate, for example, as alternatives to bromide. Avariety of different catalysts, which includes other metals such asnickel, ligands, bases, and solvents can be employed in this reaction.

Specific compounds in the present invention may be prepared by thegeneral method described above, according to Scheme 5, in which pinacolboronate ester 5.1 is reacted with 3-bromopyridine 5.2 underpalladium-catalyzed conditions followed by treatment with hydrazinehydrate to afford product 5.3.

Intermediates like 6.2 in the present invention may be preparedaccording to Scheme 6, in which bromide 6.1 is treated with sodiumhydride and n-butyllithium at below ambient temperature followed byreaction with triisopropylborate and subsequent treatment with aqueousHCl to afford boronic acid 6.2. Other alkyllithium bases, boron sources,and acids can be employed in this transformation.

Intermediates like 3.1 in the present invention may be preparedaccording to Scheme 7, in which aldehyde 7.1 is treated with aqueoussodium hydroxide in acetone followed by reaction of the resultingstyrene with trimethylsulfoxonium iodide in the presence of sodiumhydride to afford cyclopropane 7.2. Other bases may be employed in thefirst step to affect that transformation and other cyclopropanationreactions can be employed, such as a Simmons-Smith reaction, as a secondstep to afford products like 7.2. Cyclopropane 7.2 is the reacted withDMF-DMA to afford α,β-unsaturated ketone 3.1.

Intermediates like 8.5 in the present invention may be preparedaccording to Scheme 8. The sequence begins with treating sulfonamide 8.1with DMF-DMA at elevated temperature to afford aryl bromide 8.2. Arylbromide 8.2 is then reacted with alkenyl boronate 8.3 underpalladium-catalyzed conditions to afford styrenyl boronate 8.4. Avariety of different catalysts, which includes other metals such asnickel, ligands, bases, and solvents can be employed in this reaction.Styrenyl boronate 8.4 can then be treated with TMSD in the presence ofpalladium acetate followed by treatment of the resulting cyclopropanewith triflic acid to afford cyclopropyl boronate 8.5. Other palladium,copper, or rhodium catalysts can be employed in the cyclopropanationreaction.

In addition, intermediates in the present invention may be preparedaccording to Scheme 9, in which boronic acid 9.1 is reacted with bromide9.2, which may be aryl or heteroaryl, under palladium-catalyzedconditions to afford aryl chloride 9.3. Similar chemistry may beperformed using a boronate ester or boronic acid derivative in place ofthe boronic acid and an iodide, triflate, or tosylate, for example, asalternatives to bromide. A variety of different catalysts, whichincludes other metals such as nickel, ligands, bases, additives, whichincludes copper or lithium salts, and solvents can be employed in thisreaction.

Specific intermediates in the present invention may be preparedutilizing the above Suzuki-Miyaura coupling method according to Scheme10, in which 3-pyridylboronic acid 10.1 is reacted with bromopyrimidine10.2 under palladium-catalyzed conditions to afford aryl chloride 10.3.

Scheme 11 illustrated the synthesis of a pyrimidine-based compound ofthe present invention. The amidine 11.1 may be readily accessed fromintermediates like carboxylic acid 1.1 using standard methodology thatis well known to one skilled in the art. Reaction of such an amidinewith ketone 11.2 under basic conditions, for example using potassiumcarbonate in methanol, affords the desired pyrimidine 11.3. A variety ofpyrimidine-based compounds with different patterns of substitution maybe accessed using similar methodology.

It is understood that the compounds and intermediates in the foregoingreaction schemes may be employed as synthetic intermediates in otherschemes that involve similar intermediates to produce alternativecompounds of the present invention.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. Additionally, various protecting group strategies familiar toone skilled in the art of organic synthesis may be employed tofacilitate the reaction or to avoid unwanted reaction products.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

The following examples are provided so that the invention might be morefully understood. These examples are illustrative only and should not beconstrued as limiting the invention in any way. Wherein a racemicmixture is produced, the enantiomers may be separated using SFC reverseor normal phase chiral resolution conditions either after isolation ofthe final product or at a suitable intermediate, followed by processingof the single isomers individually. It is understood that alternativemethodologies may also be employed in the synthesis of these keyintermediates and examples. Asymmetric methodologies (e.g. chiralcatalysis, auxiliaries) may be used where possible and appropriate. Theexact choice of reagents, solvents, temperatures, and other reactionconditions, depends upon the nature of the intended product.

The following abbreviations are used throughout the text:

Ac Acetyl AIBN 2,2′-azobisisobutyronitrile app Apparent aq Aqueous ArAryl B₂(Pin)₂ bis(pinacolato)diboron BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthalene Bn Benzyl Boctert-butoxycarbonyl BOP(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphatebr Broad BSA bovine serum albumin Bu Butyl ca circa (approximately) CANammonium cerium(IV) nitrate Cbz Carboxybenzyl CDI1,1′-carbonyldiimidazole d Doublet DABCO diazabicyclo[2.2.2]octane DAST(diethylamino)sulfur trifluoride dba Dibenzylideneacetone DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCDMH1,3-dichloro-5,5-dimethylhydantoin dd doublet of doublets DIBALdiisobutylaluminum hydride DIEA N,N-diisopropylethylamine DMAN,N-dimethylacetamide DMAP 4-(dimethylamino)pyridine DMEM Dulbecco'smodified eagle medium (high glucose) DMF N,N-dimethylformamide DMF-N,N-dimethylformamide dimethylacetal DMA DMPU N,N′-dimethylpropyleneureaDMSO Dimethylsulfoxide DPBF 1,3-diphenylisobenzofuran dppf1,1′-bis(diphenylphosphino)ferrocene EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acidEGTA ethylene glycol-bis(β-aminoethyl ether)- N,N,N′,N′-tetraacetic acideq Equivalents ESI electrospray ionization Et Ethyl FBS fetal bovineserum h Hours HATUO-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate HEK human embryonic kidney HEPESN-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) HMDSHexamethyldisilazane HMTA Hexamethylenetetramine HOAt1-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole HPLC highperformance liquid chromatography Hz Hertz imid Imidazole i-Pr IsopropylJ coupling constant LAH lithium aluminum hydride LCMS liquidchromatography-mass spectrometry LDA lithium diisopropylamide m/z massto charge ratio m Multiplet mCPBA 3-chloroperoxybenzoic acid Me Methylmin Minutes MP macroporous polystyrene Ms Methanesulfonyl MTBE methyltert-butyl ether MW molecular weight NBS N-bromosuccinimide NHSN-hydroxysuccinimide n-BuLi n-butyllithium n-HexLi n-hexyllithium NMMN-methyl morpholine NMP 1-methyl-2-pyrrolidinone NMR nuclear magneticresonance OAc Acetate p Pentet PBPB pyridinium bromide perbromide PBSphosphate-buffered saline PCC pyridinium chlorochromate PDC pyridiniumdichromate Pd/C palladium on carbon Ph Phenyl PMBCl 4-methoxybenzylchloride psi pounds per square inch p-Ts para-toluenesulfonyl PTSApara-toluensulfonic acid Py Pyridyl q Quartet RIC-3 resistance toinhibitors of cholinesterase 3 rt room temperature S Singlet SEM2-trimethylsilylethoxymethyl SEMCl 2-trimethylsilylethoxymethyl chlorideSFC supercritical fluid chromatography SM starting material SPE solidphase extraction t Triplet T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBAF n-tetrabutylammonium fluorideTBDPS tert-butyldiphenylsilyl TBDPSCl tert-butyldiphenylsilyl chloridet-Bu tert-butyl TCCA trichloroisocyanuric acid TEA Trimethylamine TFAtrifluoroacetic acid Tf Trifluoromethanesulfonyl TCFHtetramethylchloroformamidinium hexafluorophosphate THF TetrahydrofuranTMG Tetramethylguanidine TMSD Trimethylsilyldiazomethane Trisyl2,4,6-triisopropylbenzenesulfonyl V/V volume to volume X-Phos2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Xantphos(9,9-dimethyl-9H-xanthene-4,5-diyl) bis(diphenylphosphane)

Intermediate 1

(trans-2-Phenylyclopropyl)boronic acid

To a solution of sodium hydride (20.2 g, 505 mmol) in tetrahydrofuran(700 mL) at −70° C. was added trans-(2-bromocyclopropyl)benzene (90.0 g,457 mmol) dropwise over the course of 30 min. A solution ofn-butyllithium (2.5 M in hexanes, 202 mL, 504 mmol) was added slowly andthe reaction mixture allowed to stir for 5 min followed by addition of asolution of triisopropyl borate (260 g, 1.38 mol) in tetrahydrofuran(260 mL) dropwise. The reaction mixture was allowed to slowly warm toambient temperature and stir for 14 h. An aqueous solution of HCl (2 M,2 L) was added slowly and the resulting mixture extracted with ethylacetate (2×500 mL). The combined organic extracts were washed withsaturated aqueous sodium chloride (500 mL), dried (sodium sulfate), andconcentrated under reduced pressure. Petroleum ether (100 mL) and water(200 mL) were added and the resulting mixture filtered. The precipitatewas washed with petroleum ether and dissolved in ethyl acetate (300 mL),dried (sodium sulfate), and concentrated under reduced pressure. Theresidue was recrystallized from a 3:1 mixture of water and ethanol toafford the title compound. MS: m/z=163.0 [M+H].

Intermediate 2

N-[(Dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzenesulfonamideStep A: 4-Bromo-N-[(dimethylamino)methylidene]benzenesulfonamide

A stirred solution of 4-bromobenzenesulfonamide (5.00 g, 21.2 mmol) inN,N-dimethylformamide dimethyl acetal (113 mL) was heated at 110° C. for18 h, then allowed to cool to ambient temperature. The resulting mixturewas concentrated under reduced pressure to give the title compound insufficient purity for use in the next step. MS: m/z=291.0 [M+H].

Step B:N-[(Dimethylamino)methylidene]-4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]benzenesulfonamide

To a stirred solution of4-bromo-N-[(dimethylamino)methylidene]benzenesulfonamide (6.10 g, 21.0mmol) in toluene (70 mL) at ambient temperature was added vinylboronicacid pinacol ester (7.11 mL, 41.9 mmol),bis(tri-tert-butylphosphine)palladium(0) (535 mg, 1.05 mmol), andtriethylamine (6.42 mL, 46.1 mmol). The resulting mixture was heated at80° C. for 18 h, then poured into water (100 mL) and extracted withethyl acetate (2×200 mL). The combined organic extracts were washed withsaturated aqueous sodium chloride (100 mL), dried (sodium sulfate),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with a gradient of ethylacetate:hexanes—0:100 to 30:70 to afford the title compound. MS:m/z=365.3 [M+H].

Step C:N-[(Dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trimethylsilyl)cyclopropyl]benzenesulfonamide

To a stirred solution ofN-[(dimethylamino)methylidene]-4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]benzenesulfonamide(6.00 g, 16.5 mmol) in tetrahydrofuran (82 mL) at ambient temperaturewas added palladium(II) acetate (924 mg, 4.12 mmol) and(trimethylsilyl)diazomethane (2.0 M in diethyl ether, 24.7 mL, 49.4mmol), sequentially. The reaction mixture was allowed to stir at ambienttemperature for 18 h, then acetic acid (12 mL) was added and theresulting mixture was poured into water (200 mL) and extracted withdichloromethane (3×200 mL). The combined organic extracts were dried(sodium sulfate), filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:hexanes—10:90 to 60:40 to afford the titlecompound. MS: m/z=451.3 [M+H].

Step D:N-[(Dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzenesulfonamide

To a stirred solution ofN-[(dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trimethylsilyl)cyclopropyl]benzenesulfonamide(1.25 g, 2.77 mmol) in dichloromethane (22 mL) at 0° C. was addedtrifluoromethanesulfonic acid (0.801 mL, 9.02 mmol). The reactionmixture was allowed to warm to ambient temperature and allowed to stirfor 2 h, then poured into saturated aqueous sodium bicarbonate (50 mL),and extracted with dichloromethane (2×100 mL). The combined organicextracts were dried (sodium sulfate), filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatography,eluting with a gradient of methanol:dichloromethane—0:100 to 4:96 toafford the title compound. MS: m/z=379.3 [M+H].

Intermediate 3

(1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxylic acid Step A: Ethyl(1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate

To a stirred solution of ethyl trans-2-phenylcyclopropanecarboxylate(700 g, 3.68 mol) in chloroform (6 L) at 0° C. was added chlorosulfonicacid (2.45 L, 36.8 mol) dropwise. The resulting mixture was allowed towarm to ambient temperature and stirring was continued for 2 h, then thereaction mixture was cooled to 0° C. and quenched by addition of water(3 L). The resulting mixture was extracted with dichloromethane (2×3 L)and the combined organic extracts were dried (sodium sulfate), filtered,and concentrated under reduced pressure. The residue was dissolved in1,4-dioxane (15 L) and ammonium hydroxide solution (30%, 2.1 L, 18.0mol) was added dropwise. The resulting mixture was stirred for 30 min atambient temperature and then diluted with water (10 L). The resultingmixture was extracted with ethyl acetate (3×5 L) and the combinedorganic extracts were washed with saturated aqueous sodium chloride (10L), dried (sodium sulfate), filtered, and concentrated under reducedpressure to provide the racemic title compound. The enantiomers wereresolved by SFC, utilizing a Chiralcel OD-H column and eluting withethanol:carbon dioxide:diethylamine—20:80:0.2. The first major peak toelute was ethyl (1S,2S)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate,and the second major peak to elute was ethyl(1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate, the titlecompound. MS: m/z=270.1 [M+H].

Step B: (1R,2R)-2-(4-Sulfamoylphenyl)cyclopropanecarboxylic acid

To a stirred solution of ethyl(1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate (190 g, 0.705 mol)in tetrahydrofuran (3 L) and methanol (600 mL) at ambient temperaturewas added at 0° C. was added aqueous sodium hydroxide (2.12 M, 1.00 L,2.12 mol) dropwise. The resulting mixture was allowed to stir at ambienttemperature for 2 h and then concentrated under reduced pressure toremove the organic solvents. The resulting mixture was adjusted to pH=4by addition of aqueous hydrochloric acid (2.0 M) and extracted withethyl acetate (2×2 L) and the combined organic extracts were washed withsaturated aqueous sodium chloride (1 L), dried (sodium sulfate),filtered, and concentrated under reduced pressure. The residue waspurified by recrystallization from diethyl ether to afford the titlecompound. MS: m/z=242.1 [M+H].

Intermediate 4

(1S,2S)-2-(4-Sulfamoylphenyl)cyclopropanecarboxylic acid

Essentially following the procedures described in Intermediate 2, butusing ethyl (1S,2S)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate(described in Intermediate 2) in place of ethyl(1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxylate, the title compoundwas obtained. MS: m/z=242.1 [M+H].

Intermediate 5

(1R,3R)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acidStep A: (1R,3R)-2,2-Dimethyl-3-phenyleyclopropanecarboxylic acid

The enantiomers of trans-2,2-dimethyl-3-phenylcyclopropanecarboxylicacid (957 g, 5.03 mol) were resolved by SFC, utilizing a Lux-5u columnand eluting with methanol:carbon dioxide—30:70. The first major peak toelute was (1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid, thetitle compound, and the second major peak to elute was(1S,3S)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid. MS: m/z=191.1[M+H].

Step B: Ethyl (1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylate

To a stirred solution of(1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid (267 g, 1.40mol) in ethanol (2.7 L) was added thionyl chloride (497 g, 4.21 mol)dropwise at 0° C. The resulting solution was allowed to stir for 1 h atambient temperature and concentrated under reduced pressure. The residuewas dissolved in ethyl acetate (2 L), washed with saturated aqueoussodium bicarbonate (2×1.5 L) and saturated aqueous sodium chloride (3L), dried (magnesium sulfate), and concentrated under reduced pressureto afford the title compound. MS: m/z=219.1 [M+H].

Step C: Ethyl(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

To a stirred solution of ethyl(1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylate (245 g, 1.12 mol)in chloroform (2.5 L) at 0° C. was added chlorosulfonic acid (1564 g,13.48 mol) dropwise. The resulting solution was allowed to stir for minat 0° C., warmed to ambient temperature, and allowed to stir for 2 h.The reaction mixture was cooled to 0° C., water (2 L) was added, and theresulting solution was extracted with ethyl acetate (2×3 L). The organicextracts were combined, washed with saturated aqueous sodium chloride (3L), dried (magnesium sulfate), and concentrated under reduced pressure.The residue was dissolved in 1,4-dioxane (9 L), cooled to 5° C., andammonium hydroxide solution (30%, 1.75 L, 13.5 mol) was added. Theresulting solution was allowed to stir for 30 min at ambienttemperature, diluted with water (5 L), and the resulting solutionextracted with ethyl acetate (3×3 L). The combined organic extracts werewashed with saturated aqueous sodium chloride (5 L), dried (magnesiumsulfate), and concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with a gradient of ethylacetate:petroleum ether—17:83 to 33:67 to afford the title compound. MS:m/z=298.0 [M+H].

Step D: (1R,3R)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylicacid

To a solution of (1R,3R)-ethyl2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate (15 g, 50.4mmol) in tetrahydrofuran (400 mL) and methanol (100 mL) at ambienttemperature was added sodium hydroxide (1.0 M, 150 mL, 150 mmol). Thereaction mixture was warmed to 60° C. and allowed to stir for 2.5 h. Thereaction mixture was cooled to 0° C., hydrochloric acid (1.00 M, 12.5mL, 151 mmol) slowly added, and the resulting mixture concentrated underreduced pressure to remove methanol, tetrahydrofuran, and a small amountof the water. The mixture was extracted with ethyl acetate (3×200 mL)and the combined organic extracts were washed with saturated aqueoussodium chloride (150 mL), dried (sodium sulfate), filtered, andconcentrated under reduced pressure to afford the title compound. MS:m/z=270.1 [M+H].

Intermediate 6

(1S,3S)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

Essentially following the procedures described in Intermediate 4, butusing (1S,3S)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid(described in Intermediate 4) in place of(1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid, the titlecompound was obtained. MS: m/z=270.2 [M+H].

Intermediate 7

(1S,3S)-2,2-Difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acidStep A: Ethyl(1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

To chlorosulfonic acid (35.5 mL, 530 mmol) at 0° C. was added ethyltrans-2,2-difluoro-3-phenylcyclopropanecarboxylate (10.0 g, 44.2 mmol)(Dolbier et al. J. Fluorine Chem. (2004) 125:459-469) dropwise. Thereaction mixture was allowed to stir at 0° C. for 30 min, warmed toambient temperature, and allowed to stir for 2 h. The reaction mixturewas slowly added to slowly stirred ice/water (500 mL) over the course of5 min. The resulting suspension was then diluted with ethyl acetate (400mL) and allowed to stir for 5 min. The layers were separated and theaqueous layer extracted with ethyl acetate (2×400 mL). The combinedorganic extracts were washed with water (400 mL), dried (magnesiumsulfate), and concentrated under reduced pressure. The residue wasdissolved in 1,4-dioxane (400 mL) and ammonium hydroxide (30%, 92 mL,1.36 mol) was added. The reaction mixture was allowed to stir at ambienttemperature for 2.5 h and then concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:hexanes—0:100 to 40:60 to afford the racemictitle compound. The racemate was resolved by SFC, utilizing a ChiralPakAD-H column, eluting with isopropanol:carbondioxide:diethylamine—20:80:0.1. The first major peak to elute was ethyl(1R,3R)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate andthe second major peak to elute was ethyl(1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate, thetitle compound. MS: m/z=306.2 [M+H].

Step B: (1S,3S)-2,2-Difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylicacid

To a solution of ethyl(1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropane carboxylate, (500mg, 1.64 mmol) in acetonitrile (8.2 mL) was added aqueous lithiumhydroxide (1.0 M, 4.9 mL, 4.9 mmol) and the reaction mixture allowed tostir at ambient temperature for 18 h. The reaction mixture wasconcentrated under reduced pressure and the aqueous layer acidified withaqueous HCl (1 M). The mixture was then extracted with ethyl acetate(3×20 mL) and the combined organic extracts washed with saturatedaqueous sodium chloride (20 mL), dried (magnesium sulfate) andconcentrated under reduced pressure to afford the title compound. MS:m/z=278.1 [M+H].

Intermediate 8

(1R,3R)-2,2-Difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid

Essentially following the procedures described in Intermediate 6, butusing ethyl(1R,3R)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate(described in Intermediate 6) in place of ethyl(1S,3S)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylate, thetitle compound was obtained. MS: m/z=278.1 [M+H].

Intermediate 9

(1R,3R)-3-{4-[(tert-Butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylicacid Step A: Ethyl(1R,3R)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylate

To a stirred solution of ethyl(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate(described in Intermediate 4) (2.00 g, 6.73 mmol) in tetrahydrofuran (24mL) at ambient temperature were added di-tert-butyl dicarbonate (7.34 g,33.6 mmol) and DMAP (82 mg, 0.67 mmol). The resulting mixture wasallowed to stir at ambient temperature for 18 h, then at 50° C. for 7 h,then allowed to cool to ambient temperature. Di-tert-butyl dicarbonate(1.50 g, 6.87 mmol) was added and the reaction mixture was allowed tostir at 50° C. for 3 h, then allowed to cool to ambient temperature.Di-tert-butyl dicarbonate (3.00 g, 13.7 mmol) and DMAP (82 mg, 0.67mmol) were added and the reaction mixture was allowed to stir at 50° C.for 3 h, then allowed to cool to ambient temperature. The resultingmixture was concentrated under reduced pressure and the residue waspurified by silica gel chromatography, eluting with a gradient of ethylacetate:hexanes—0:100 to 30:70 to afford the title compound. MS:m/z=517.3 [M+CH₃CN+Na].

Step B:(1R,3R)-3-{4-[(tert-Butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylicacid

To a stirred solution of ethyl(1R,3R)-3-{4-[(tert-butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylate(2.36 g, 5.19 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL) atambient temperature was added aqueous sodium hydroxide (2.0 M, 9.47 mL,18.9 mmol) dropwise. The resulting mixture was allowed to stir atambient temperature for 18 h and then poured into water (50 mL). Theresulting mixture was adjusted to pH=4 by addition of aqueoushydrochloric acid (1.0 M) and extracted with ethyl acetate (2×100 mL).The combined organic extracts were washed with saturated aqueous sodiumchloride (40 mL), dried (sodium sulfate), filtered, and concentratedunder reduced pressure to provide the title compound, which was usedwithout further purification. MS: m/z=489.2 [M+CH₃CN+Na].

Intermediate 10

(1S,3S)-3-{4-[(tert-Butoxycarbonyl)(tert-butyl)sulfamoyl]phenyl}-2,2-dimethylcyclopropanecarboxylicacid

Essentially following the procedures described in Intermediate 8, butusing ethyl(1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate(described in Intermediate 5) in place of ethyl(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate, thetitle compound was obtained. MS: m/z=489.4 [M+CH₃CN+Na].

Intermediate 11

2-Chloro-4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidine

To a solution of [5-(trifluoromethyl)pyridin-3-yl]boronic acid (457 mg,2.39 mmol) in DME (8.0 mL) and water (2.0 mL) were added4-bromo-2-chloropyrimidine (463 mg, 2.39 mmol) and cesium carbonate(2.34 g, 7.18 mmol) and the mixture deoxygenated.1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride,dichloromethane complex (392 mg, 0.479 mmol) was added and the reactionmixture allowed to stir at ambient temperature for 14 h. The reactionmixture was diluted with ethyl acetate (15 mL), washed with water (10mL), dried (magnesium sulfate), and concentrated under reduced pressure.The residue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:hexanes—0:100 to 50:50 to afford the titlecompound in sufficient purity for use in the next step. MS: m/z=260.0[M+H].

Intermediate 12

N-[(Dimethylamino)methylidene]-4-{trans-2-[3-(dimethylamino)prop-2-enoyl]cyclopropyl}benzenesulfonamideStep A: 4-[(1E)-3-Oxobut-1-en-1-yl]benzenesulfonamide

To a sealable vial containing 4-formylbenzenesulfonamide (2.00 g, 10.8mmol) dissolved in acetone (10.5 mL) and water (21.1 mL) was added anaqueous solution of sodium hydroxide (5%, 4.32 mL, 108 mmol). Thereaction mixture was warmed to 40° C. and allowed to stir for 2 days.The reaction mixture was cooled to ambient temperature, diluted withethyl acetate (20 mL), and treated with aqueous HCl (1 N) until the pHof the mixture was approximately 6. The layers were separated and theorganic phase dried (sodium sulfate) and concentrated under reducedpressure to afford the title compound in sufficient purity for use inthe next step. MS: m/z=226.1 [M+H].

Step B:4-(trans-2-Acetylcyclopropyl)-N-[(dimethylamino)methylidene]benzenesulfonamide

To a solution of trimethylsulfoxonium iodide (2.56 g, 11.6 mmol) in DMSO(48.4 mL) was added sodium hydride (0.852 g, 21.3 mmol) and the reactionmixture allowed to stir for 5 min.4-[(1E)-3-Oxobut-1-en-1-yl]benzenesulfonamide (2.18 g, 9.68 mmol) wasadded portionwise and the reaction mixture allowed to stir for 14 h. Thereaction mixture was diluted with ethyl acetate (100 mL) and water (100mL) and the layers separated. The aqueous layer was extracted with ethylacetate (7×100 mL) and the combined organic extracts washed withsaturated aqueous sodium chloride (100 mL), dried (sodium sulfate), andconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with a gradient of ethylacetate:ethanol:hexanes—0:0:100 to 75:25:0 to afford the title compound.MS: m/z=240.1 [M+H].

Step C:N-[(Dimethylamino)methylidene]-4-{trans-2-[3-(dimethylamino)prop-2-enoyl]cyclopropyl}benzenesulfonamide

To a sealable vial containing4-(trans-2-acetylcyclopropyl)-N-[(dimethylamino)methylidene]benzenesulfonamide(553 mg, 2.31 mmol) was added DMF-DMA (6.19 mL, 46.2 mmol). The reactionmixture was warmed to 110° C. and allowed to stir for 14 h. The reactionmixture was cooled to ambient temperature, diluted with dichloromethane(15 mL), washed with water (3×10 mL), dried (sodium sulfate), andconcentrated under reduced pressure to afford the title compound insufficient purity for use in the next step. MS: m/z=350.2 [M+H].

Intermediate 13

(1R,3R)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboximidamideStep A:(1R,3R)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

To a stirred solution of(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid(Intermediate 5) (850 mg, 3.16 mmol) in tetrahydrofuran (10 mL) wasadded 1,1′-carbonyldiimidazole (614 mg, 3.79 mmol) and the resultingmixture was stirred at ambient temperature for 1 h. Aqueous ammoniumhydroxide (28% solution, 8.8 mL, 130 mmol) was added and the reactionmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated under reduced pressure to remove tetrahydrofuran and theresidual mixture was adjusted to pH=3 by addition of 1 M aqueoushydrochloric acid. The aqueous layer was extracted with ethyl acetate(3×10 mL) and the combined organic extracts were washed with saturatedaqueous potassium carbonate (2×10 mL), dried (sodium sulfate), filtered,and the solvent evaporated under reduced pressure to afford the titlecompound in sufficient purity for use in the next step. MS: m/z=269.1[M+H].

Step B:4-[(1R,3R)-3-Cyano-2,2-dimethylcyclopropyl]-N-[(dimethylamino)methylidene]benzenesulfonamide

To a stirred solution of(1R,2R)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide (500 mg, 1.86 mmol)in N,N-dimethylformamide (8 mL) at ambient temperature was added thionylchloride (3.3 g, 27 mmol) dropwise and the resulting solution wasallowed to stir for 1 h at ambient temperature. The reaction mixture wasdiluted with water (10 mL) and extracted with ethyl acetate (3×10 mL).The combined organic extracts were washed with saturated aqueous sodiumchloride (25 mL), dried (sodium sulfate), and concentrated under reducedpressure. The residue was purified by silica gel chromatography, elutingwith ethyl acetate, to afford the title compound. MS: m/z=306.1 [M+H].

Step C: Ethyl(1R,3R)-3-(4-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2,2-dimethylcyclopropanecarboximidoate

A solution of4-[(1R,3R)-3-cyano-2,2-dimethylcyclopropyl]-N-[(dimethylamino)methylidene]benzenesulfonamide(180 mg, 0.59 mmol) in ethanol (10 mL) at 0° C. was saturated withhydrogen chloride (g) and the resulting mixture was allowed to stir atambient temperature for 4 h. The reaction mixture was concentrated underreduced pressure to afford the title compound in sufficient purity foruse in the next step. MS: m/z=352.1 [M+H].

Step D:(1R,3R)-2,2-Dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboximidamide

To a mixture of ethyl(1R,3R)-3-(4-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2,2-dimethylcyclopropanecarboximidoate(200 mg, 0.57 mmol) and ethanol (5 mL) at 0° C. was added a saturatedsolution of ammonia in methanol (5 mL). The reaction mixture was allowedto stir at 50° C. for 12 h and was then concentrated under reducedpressure to afford the title compound in sufficient purity for use inthe next step. MS: m/z=268.0 [M+H].

Intermediate 14

3-(Dimethylamino)-1-[5-(trifluoromethyl)pyridin-3-yl]prop-2-en-1-oneStep A: 3-(1-Ethoxyethenyl)-5-(trifluoromethyl)pyridine

To a solution of 3-bromo-5-(trifluoromethyl)pyridine (500 mg, 2.21 mmol)in N,N-dimethylformamide (8 mL) were addedbis(triphenylphosphine)palladium(II) dichloride (15.5 mg, 0.022 mmol)and tributyl(1-ethoxyvinyl)tin (959 mg, 2.66 mmol) at ambienttemperature. The reaction mixture was allowed to stir at 100° C. for 2h, then allowed to cool to ambient temperature and saturated aqueouspotassium fluoride (10 mL) was added. The resulting mixture was filteredand the filtrate was diluted with ethyl acetate (30 mL) and the organiclayer was washed with saturated aqueous sodium hydrogen carbonate (2×10mL), then saturated aqueous sodium chloride (2×10 mL), then dried(sodium sulfate), filtered, and the solvent evaporated under reducedpressure to afford the title compound in sufficient purity for use inthe next step. MS: m/z=217.8 [M+H].

Step B: 1-[5-(Trifluoromethyl)pyridin-3-yl]ethanone

To a stirred solution of 3-(1-ethoxyethenyl)-5-(trifluoromethyl)pyridine(450 mg, 2.07 mmol) in tetrahydrofuran (8 mL) at ambient temperature wasadded 2 M aqueous hydrochloric acid (5 mL, 10 mmol) and the resultingsolution was allowed to stir for 12 h at ambient temperature. Thereaction mixture was diluted with water (10 mL) and extracted with ethylacetate (3×10 mL). The combined organic extracts were dried (sodiumsulfate), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography, eluting with ethylacetate:petroleum ether—1:5, to afford the title compound. MS: m/z=190.0[M+H].

Step C:3-(Dimethylamino)-1-[5-(trifluoromethyl)pyridin-3-yl]prop-2-en-1-one

A mixture of 1-[5-(trifluoromethyl)pyridin-3-yl]ethanone (150 mg, 0.79mmol) and tert-butoxy bis(dimethylamino)methane (138 mg, 0.79 mmol) wasallowed to stir at 110° C. for 12 h. The reaction mixture was allowed tocool to ambient temperature and was concentrated under reduced pressureto afford the title compound in sufficient purity for use in the nextstep. MS: m/z=245.1 [M+H].

Intermediate 15

(1R,3R)-2,2-Difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboximidamide

Essentially following the procedures described in Intermediate 13, butusing (1R,3R)-2,2-difluoro-3-(4-sulfamoylphenyl)cyclopropanecarboxylicacid (Intermediate 8) in place of(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylic acid,the title compound was obtained. MS: m/z=276.1 [M+H].

Intermediate 16

3-(Dimethylamino)-1-(3-fluorophenyl)prop-2-en-1-one

Essentially following the procedures described in Intermediate 14, butusing 3-fluoroacetophenone in place of1-[5-(trifluoromethyl)pyridin-3-yl]ethanone, the title compound wasobtained. MS: m/z=194.1 [M+H].

The intermediates appearing in the following tables were prepared byanalogy to the above intermediates, as described or prepared as a resultof similar transformations with modifications known to those skilled inthe art. The requisite starting materials were described herein,commercially available, known in the literature, or readily synthesizedby one skilled in the art. Straightforward protecting group strategieswere applied in some routes.

TABLE INT-A

Intermediate X R¹ R² R³ R⁴ R⁵ MS [M + H] A1 Cl H F H H H 209.0

Example 1

4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide,Enantiomer B Step A:2-(trans-2-Phenylcyclopropyl)-6-(propan-2-yl)pyridine

To a solution of (trans-2-phenylcyclopropyl)boronic acid(Intermediate 1) (211 mg, 1.30 mmol) in toluene (3.3 mL) were added2-bromo-6-isopropylpyridine (137 mg, 0.685 mmol) and tribasic potassiumphosphate (436 mg, 2.05 mmol) and the reaction mixture deoxygenated withnitrogen. Palladium(II) acetate (30.7 mg, 0.137 mmol),di(1-adamantyl)-n-butylphosphine (98 mg, 0.27 mmol), and water (0.2 mL)were added and the reaction mixture deoxygenated with nitrogen, sealed,warmed to 100° C., and allowed to stir for 4 h. The reaction mixture wasconcentrated under reduced pressure and the residue purified by silicagel chromatography, eluting with a gradient of ethylacetate:hexanes—0:100 to 50:50 to afford the title compound. MS:m/z=238.2 [M+H].

Step B:4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide,Enantiomer B

To a flask containingtrans-2-(2-phenylcyclopropyl)-6-(propan-2-yl)pyridine (145 mg, 0.611mmol) was added chlorosulfonic acid (1.00 mL, 14.9 mmol) and thereaction mixture was allowed to stir for 30 min. The reaction mixturewas added dropwise to ice water (15 mL) and the mixture decanted. Theresidue was dissolved in 1,4-dioxane (2 mL) and to the resultingsolution was added ammonium hydroxide (15 M, 0.50 mL, 7.6 mmol). Thereaction mixture was allowed to stir for 30 min then diluted with water(10 mL). The reaction mixture was extracted with ethyl acetate (2×15 mL)and the combined organic extracts washed with saturated aqueous sodiumchloride (10 mL), dried (magnesium sulfate), and concentrated underreduced pressure. The residue was purified by silica gel chromatography,eluting with a gradient of ethyl acetate:ethanol:hexanes—3:1:96 to57:19:24 to afford the title compound. The racemate was resolved by SFC,utilizing a ChiralPak AD-H column, eluting with methanol:carbondioxide:isopropylamine—35:65:0.25. The first major peak to elute wastrans-4-{2-[6-(propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide,enantiomer A, and the second major peak to elute wastrans-4-{2-[6-(propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide,enantiomer B, the title compound. MS: m/z=317.2 [M+H]. ¹H NMR (500 MHz,DMSO-d₆): δ 7.71 (d, J=8.1 Hz, 2H); 7.58 (t, J=7.7 Hz, 1H); 7.37 (d,J=8.2 Hz, 2H); 7.27 (s, 2H); 7.15 (d, J=7.6 Hz, 1H); 7.05 (d, J=7.7 Hz,1H); 2.92-2.97 (m, 1H); 2.42-2.48 (m, 2H); 1.74 (dt, J=8.9, 4.8 Hz, 1H);1.50-1.54 (m, 1H); 1.23 (d, J=1.7 Hz, 3H); 1.22 (d, J=1.8 Hz, 3H).

Example 2

4-{trans-2-[2-(Morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide

To a solution ofN-[(dimethylamino)methylidene]-4-{trans-2-[3-(dimethylamino)prop-2-enoyl]cyclopropyl}benzenesulfonamide(Intermediate 12) (30 mg, 0.086 mmol) in ethanol (1.1 mL) were addedpotassium carbonate (23.7 mg, 0.172 mmol) andmorpholine-4-carboximidamide (16.7 mg, 0.129 mmol). The reaction mixturewas warmed to 80° C. and allowed to stir for 14 h. The reaction mixturewas cooled to ambient temperature, concentrated under a stream ofnitrogen, and the resulting residue purified by preparative HPLC,eluting with a gradient of acetonitrile:water:trifluoroaceticacid—10:90:0.1 to 40:60:0.1 to afford the title compound. MS: m/z=360.1[M+H]. ¹H NMR (500 MHz, DMSO-d₆): δ 8.20 (d, J=5.0 Hz, 1H); 7.72 (d,J=8.1 Hz, 2H); 7.37 (d, J=8.2 Hz, 2H); 7.28 (s, 2H); 6.69 (d, J=5.0 Hz,1H); 3.66-3.68 (br m, 8H); 2.33 (br s, 2H); 1.77 (br s, 1H); 1.58 (br s,1H).

Example 3

4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,Enantiomer B Step A: 2-Cyclopentyl-6-(trans-2-phenylcyclopropyl)pyridine

To a solution of (trans-2-phenylcyclopropyl)boronic acid(Intermediate 1) (681 mg, 4.20 mmol) in a mixture of toluene (10.5 mL)and water (0.6 mL) were added 2-bromo-6-cyclopentylpyridine (500 mg,2.21 mmol) and tribasic potassium phosphate (1.41 g, 6.63 mmol) and thereaction mixture deoxygenated with nitrogen. Palladium(II) acetate (99mg, 0.44 mmol) and di(1-adamantyl)-n-butylphosphine (317 mg, 0.885 mmol)were added and the reaction mixture warmed to 110° C. and allowed tostir for 4 h. The reaction mixture was diluted with ethyl acetate (20mL), washed with water (10 mL) and saturated aqueous sodium chloride (10mL), dried (magnesium sulfate), and concentrated under reduced pressure.The residue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:hexanes—5:95 to 100:0 to afford the titlecompound. MS: m/z=264.3 [M+H].

Step B:4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,Enantiomer B

To a flask containing2-cyclopentyl-6-(trans-2-phenylcyclopropyl)pyridine (324 mg, 1.23 mmol)was added chlorosulfonic acid (2.00 mL, 29.9 mmol) and the reactionmixture allowed to stir for 30 min. The reaction mixture was addeddropwise to ice water (20 mL) and the mixture decanted. The residue wasdissolved in 1,4-dioxane (3 mL) and to the resulting solution was addedammonium hydroxide (15 M, 1.50 mL, 22.7 mmol). The reaction mixture wasallowed to stir for 30 min then diluted with water (15 mL). The reactionmixture was extracted with ethyl acetate (2×20 mL) and the combinedorganic extracts washed with saturated aqueous sodium chloride (15 mL),dried (magnesium sulfate), and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:ethanol:hexanes—3:1:96 to 57:19:24 to affordthe title compound. The racemate was resolved by SFC, utilizing aChiralPak AD-H column, eluting with methanol:isopropanol:carbondioxide:isopropylamine—25:25:50:0.25. The first major peak to elute was4-[trans-2-(6-cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,enantiomer A, and the second major peak to elute was4-[trans-2-(6-cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,enantiomer B, the title compound. MS: m/z=343.2 [M+H]. ¹H NMR (500 MHz,DMSO-d₆): δ 7.71 (d, J=8.2 Hz, 2H); 7.55 (t, J=7.6 Hz, 1H); 7.36 (d,J=8.2 Hz, 2H); 7.27 (s, 2H); 7.14 (d, J=7.6 Hz, 1H); 7.04 (d, J=7.7 Hz,1H); 3.08-3.14 (m, 1H); 2.41-2.48 (m, 2H); 1.93-1.97 (m, 2H); 1.70-1.76(m, 5H); 1.63-1.67 (m, 2H); 1.50-1.54 (m, 1H).

Example 4

4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,Enantiomer B Step A: 5-Cyclopentyl-2-(trans-2-phenylcyclopropyl)pyridine

To a solution of (trans-2-phenylcyclopropyl)boronic acid(Intermediate 1) (681 mg, 4.20 mmol) in a mixture of toluene (10.5 mL)and water (0.6 mL) were added 2-bromo-6-cyclopentylpyridine (500 mg,2.21 mmol) and tribasic potassium phosphate (1.41 g, 6.63 mmol) and thereaction mixture deoxygenated with nitrogen. Palladium(II) acetate (99mg, 0.44 mmol) and di(1-adamantyl)-n-butylphosphine (317 mg, 0.885 mmol)were added and the reaction mixture warmed to 110° C. and allowed tostir for 4 h. The reaction mixture was diluted with ethyl acetate (20mL), washed with water (10 mL) and saturated aqueous sodium chloride (10mL), dried (magnesium sulfate), and concentrated under reduced pressure.The residue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:hexanes—5:95 to 100:0 to afford the titlecompound. MS: m/z=264.3 [M+H].

Step B:4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,Enantiomer B

To a flask containing5-cyclopentyl-2-(trans-2-phenylcyclopropyl)pyridine (391 mg, 1.49 mmol)was added chlorosulfonic acid (2.00 mL, 29.9 mmol) and the reactionmixture was allowed to stir for 30 min. The reaction mixture was addeddropwise to ice water (20 mL) and the mixture decanted. The residue wasdissolved in 1,4-dioxane (3 mL) and to the resulting solution was addedammonium hydroxide (15 M, 1.50 mL, 22.7 mmol). The reaction mixture wasallowed to stir for 30 min then diluted with water (15 mL). The reactionmixture was extracted with ethyl acetate (2×20 mL) and the combinedorganic extracts washed with saturated aqueous sodium chloride (15 mL),dried (magnesium sulfate), and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:ethanol:hexanes—3:1:96 to 57:19:24 to affordthe title compound. The racemate was resolved by SFC, utilizing aChiralPak AD-H column, eluting with ethanol:carbondioxide:isopropylamine—55:45:0.25. The first major peak to elute was4-[trans-2-(5-cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,enantiomer A and the second major peak to elute was4-[trans-2-(5-cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide,enantiomer B, the title compound. MS: m/z=343.2 [M+H]. ¹H NMR (500 MHz,DMSO-d₆): δ 8.36 (d, J=2.3 Hz, 1H); 7.71 (d, J=8.1 Hz, 2H); 7.55 (dd,J=8.0, 2.4 Hz, 1H); 7.36 (d, J=8.2 Hz, 2H); 7.29 (d, J=8.2 Hz, 1H); 7.27(s, 2H); 2.91-2.98 (m, 1H); 2.41-2.48 (m, 2H); 2.01 (br s, 2H);1.74-1.80 (m, 2H); 1.68-1.72 (m, 1H); 1.65 (m, 2H); 1.50-1.54 (m, 3H).

Example 5

4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,Enantiomer B Step A:2-(trans-2-Phenylcyclopropyl)-4-(propan-2-yl)pyrimidine

To a solution of (trans-2-phenylcyclopropyl)boronic acid(Intermediate 1) (1.53 g, 9.45 mmol) in a mixture of toluene (8.0 mL)and water (0.4 mL) were added 2-bromo-4-isopropylpyrimidine (1.0 g, 4.97mmol) and tribasic potassium phosphate (3.17 g, 14.9 mmol) and thereaction mixture was deoxygenated with nitrogen. Palladium(II) acetate(223 mg, 0.995 mmol) and di(1-adamantyl)-n-butylphosphine (713 mg, 1.99mmol) were added and the reaction mixture was warmed to 100° C. andallowed to stir for 14 h. The reaction mixture was diluted with ethylacetate (20 mL), washed with water (10 mL) and saturated aqueous sodiumchloride (10 mL), dried (magnesium sulfate), and concentrated underreduced pressure. The residue was purified by silica gel chromatography,eluting with a gradient of ethyl acetate:hexanes—0:100 to 50:50 toafford the title compound. MS: m/z=239.1 [M+H].

Step B:4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,Enantiomer B

To a flask containing chlorosulfonic acid (8.00 mL, 119 mmol) at 0° C.was added 2-(trans-2-phenylcyclopropyl)-4-(propan-2-yl)pyrimidine (890mg, 3.73 mmol) dropwise and the reaction mixture was allowed to stir for30 min. The reaction mixture was warmed to ambient temperature andallowed to stir for 1 h. The reaction mixture was added dropwise to icewater (20 mL) and the mixture decanted. The residue was dissolved in1,4-dioxane (8 mL) and to the resulting solution was added ammoniumhydroxide (15 M, 4.00 mL, 60.4 mmol). The reaction mixture was allowedto stir for 30 min then diluted with ethyl acetate (25 mL). The layerswere separated and the aqueous phase was extracted with ethyl acetate(2×30 mL). The combined organic extracts were washed with water (20 mL)and saturated aqueous sodium chloride (20 mL), dried (magnesiumsulfate), and concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with a gradient of ethylacetate:ethanol:hexanes—3:1:96 to 38:12:50 to afford the title compound.The racemate was resolved by SFC, utilizing a ChiralPak AD-H column,eluting with ethanol:carbon dioxide:isopropylamine—50:50:0.25. The firstmajor peak to elute was4-{trans-2-[4-(propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,enantiomer A and the second major peak to elute was4-{trans-2-[4-(propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,enantiomer B, the title compound. MS: m/z=318.2 [M+H]. ¹H NMR (500 MHz,DMSO-d₆): δ 8.56 (d, J=5.2 Hz, 1H); 7.72 (d, J=8.2 Hz, 2H); 7.40 (d,J=8.2 Hz, 2H); 7.29 (s, 2H); 7.21 (d, J=5.2 Hz, 1H); 2.90-2.97 (m, 1H);2.57-2.61 (m, 1H); 2.51-2.54 (m, 1H); 1.75-1.79 (m, 1H); 1.61 (ddd,J=8.6, 6.1, 4.1 Hz, 1H); 1.23 (d, J=1.9 Hz, 3H); 1.22 (d, J=1.9 Hz, 3H).

Example 6

4-{trans-2-[6-(Pyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide

To a solution ofN-[(dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzenesulfonamide(Intermediate 2) (30 mg, 0.079 mmol) in toluene (0.79 mL) were added5-bromo-2-(pyrrolidin-1-yl)pyridine (32 mg, 0.12 mmol),chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(5.3 mg, 0.0079 mmol) and an aqueous solution of tribasic potassiumphosphate (1 M, 0.238 mL, 0.238 mmol) sequentially. The reaction mixturewas warmed to 100° C. and allowed to stir for 18 h. The reaction mixturewas diluted with ethyl acetate (3 mL), filtered through an SPE cartridgecontaining celite, and the filtrate concentrated under reduced pressure.The residue was treated with a solution of hydrazine hydrate (37% inwater/ethanol, 1.5 mL, 17.6 mmol) and allowed to stir for 1.5 h. Thereaction mixture was concentrated under reduced pressure and theresulting residue was purified by preparative HPLC, eluting with agradient of acetonitrile:water:trifluoroacetic acid—5:95:0.1 to35:65:0.1 to afford the title compound. MS: m/z=344.1 [M+H]. ¹H NMR (500MHz, DMSO-d₆): δ 7.86 (s, 1H); 7.78 (d, J=9.3 Hz, 1H); 7.73 (d, J=8.0Hz, 2H); 7.35 (d, J=8.0 Hz, 2H); 7.29 (s, 2H); 7.04 (d, J=9.2 Hz, 1H);3.50 (br s, 4H); 2.34 (m, 2H); 2.02 (br s, 4H); 1.57 (m, 2H).

Example 7

4-{trans-2-[3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]cyclopropyl}benzenesulfonamide

To a solution ofN-[(dimethylamino)methylidene]-4-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzenesulfonamide(Intermediate 2) (30 mg, 0.079 mmol) in toluene (0.79 mL) were added3-(3-bromophenyl)-5-methyl-1,2,4-oxadiazole (33 mg, 0.12 mmol),chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(5.3 mg, 0.0079 mmol) and an aqueous solution of tribasic potassiumphosphate (1 M, 0.238 mL, 0.238 mmol) sequentially. The reaction mixturewas warmed to 100° C. and allowed to stir for 18 h. The reaction mixturewas diluted with ethyl acetate (3 mL), filtered through an SPE cartridgecontaining celite, and the filtrate concentrated under reduced pressure.The residue was treated with a solution of hydrazine hydrate (37% inwater/ethanol, 1.5 mL, 17.6 mmol) and allowed to stir for 1.5 h. Thereaction mixture was concentrated under reduced pressure and theresulting residue was purified by preparative HPLC, eluting with agradient of acetonitrile:water:trifluoroacetic acid—5:95:0.1 to55:45:0.1 to afford the title compound. MS: m/z=356.2 [M+H]. H NMR (500MHz, DMSO-d₆): δ 7.81 (d, J=9.0 Hz, 2H); 7.73 (d, J=8.0 Hz, 2H); 7.49(t, J=7.8 Hz, 1H); 7.40 (t, J=8.5 Hz, 3H); 7.28 (s, 2H); 2.67 (s, 3H);2.46 (s, 1H); 2.39 (s, 1H); 1.62 (s, 2H).

Example 8

4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide,Enantiomer B Step A:4-(trans-2-Phenylcyclopropyl)-2-(propan-2-yl)pyridine

To a solution of (trans-2-phenylcyclopropyl)boronic acid(Intermediate 1) (769 mg, 4.75 mmol) in a mixture of toluene (9.5 mL)and water (0.5 mL) were added 2-bromo-4-isopropylpyrimidine (500 mg,2.50 mmol) and tribasic potassium phosphate (1.59 g, 7.50 mmol) and thereaction mixture deoxygenated with nitrogen. Palladium(II) acetate (112mg, 0.500 mmol) and di(1-adamantyl)-n-butylphosphine (358 mg, 1.00 mmol)were added and the reaction mixture warmed to 100° C. and allowed tostir for 14 h. The reaction mixture was diluted with ethyl acetate (20mL), washed with water (10 mL) and saturated aqueous sodium chloride (10mL), dried (magnesium sulfate), and concentrated under reduced pressure.The residue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:hexanes—0:100 to 50:50 to afford the titlecompound. MS: m/z=238.0 [M+H].

Step B:4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide,Enantiomer B

To a solution of 4-(trans-2-phenylcyclopropyl)-2-(propan-2-yl)pyridine(472 mg, 1.99 mmol) in dichloromethane (4.0 mL) at 0° C. was addedchlorosulfonic acid (2.00 mL, 29.9 mmol) dropwise and the reactionmixture was allowed to stir for 30 min. The reaction mixture was warmedto ambient temperature and allowed to stir for 30 min. The reactionmixture was cooled to 0° C. and added dropwise to ice water (15 mL) andthe layers separated. The aqueous phase was extracted withdichloromethane (3×15 mL) and the combined organic extracts concentratedunder reduced pressure. The residue was dissolved in 1,4-dioxane (3.0mL) and to the resulting solution was added ammonium hydroxide (15 M,1.00 mL, 15.1 mmol). The reaction mixture was allowed to stir for 14 hthen diluted with ethyl acetate (25 mL). The layers were separated andthe aqueous phase was extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were washed with water (20 mL) and saturatedaqueous sodium chloride (20 mL), dried (magnesium sulfate), andconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with a gradient of ethylacetate:ethanol:hexanes—3:1:96 to 38:12:50 to afford the title compound.The racemate was resolved by SFC, utilizing a ChiralPak AD-H column,eluting with methanol:carbon dioxide:isopropylamine—30:70:0.25. Thefirst major peak to elute was4-{trans-2-[2-(propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide,enantiomer A and the second major peak to elute was4-{trans-2-[2-(propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide,enantiomer B, the title compound. MS: m/z=317.2 [M+H]. ¹H NMR (500 MHz,DMSO-d₆): δ 8.34 (d, J=5.2 Hz, 1H); 7.72 (d, J=8.2 Hz, 2H); 7.37 (d,J=8.2 Hz, 2H); 7.28 (s, 2H); 7.10 (s, 1H); 6.98-6.99 (m, 1H); 2.93-2.98(m, 1H); 2.40-2.43 (m, 1H); 2.27-2.31 (m, 1H); 1.61-1.67 (m, 2H); 1.22(s, 3H); 1.21 (s, 3H).

Example 9

4-[(1R,3R)-2,2-Dimethyl-3-{4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl]benzenesulfonamide

To a solution of3-(dimethylamino)-1-[5-(trifluoromethyl)pyridin-3-yl]prop-2-en-1-one(Intermediate 14) (15 mg, 0.06 mmol) in methanol (1 mL) at ambienttemperature were added(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboximidamide(Intermediate 13) (33 mg, 0.12 mmol) and potassium carbonate (8.5 mg,0.06 mmol). The stirred reaction mixture was heated at 60° C. for 12 h,allowed to cool to ambient temperature, and was then purified bypreparative HPLC, by preparative HPLC, eluting with a gradient ofacetonitrile:water:ammonium hydroxide—35:65:0.05 to 65:35:0.05, and theproduct-containing fractions were concentrated under reduced pressure toafford the title compound. MS: m/z=449.0 [M+H]. ¹H NMR (400 MHz, CD₃OD):δ 9.61 (s, 1H); 9.05 (s, 1H); 8.83-8.90 (m, 2H); 7.98 (d, J=5.3 Hz, 1H);7.87 (d, J=8.3 Hz, 2H); 7.51 (d, J=7.9 Hz, 2H); 3.27-3.29 (m, 1H); 2.91(d, J=6.1 Hz, 1H); 1.34 (s, 3H); 1.07 (s, 3H).

Example 10

4-{trans-2-[4-(3-Fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,Enantiomer A Step A:4-(3-fluorophenyl)-2-(trans-2-phenylcyclopropyl)pyrimidine

To a solution of (trans-2-phenylcyclopropyl)boronic acid(Intermediate 1) (153 mg, 0.94 mmol) in a mixture of toluene (4.75 mL)and water (0.25 mL) were added 2-chloro-4-(3-fluorophenyl)pyrimidine(Intermediate A1) (131 mg, 0.63 mmol) and tribasic potassium phosphate(400 mg, 1.88 mmol) and the reaction mixture was deoxygenated withnitrogen. Palladium(II) acetate (28 mg, 0.13 mmol) anddi(1-adamantyl)-n-butylphosphine (90 mg, 0.25 mmol) were added and thereaction mixture was warmed to 100° C. and allowed to stir for 18 h. Thereaction mixture was diluted with ethyl acetate (10 mL), washed withwater (5 mL) and saturated aqueous sodium chloride (5 mL), dried(magnesium sulfate), and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:hexanes—0:100 to 50:50 to afford the titlecompound. MS: m/z=291.2 [M+H].

Step B:4-{trans-2-[4-(3-Fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,Enantiomer A

To a solution of4-(3-fluorophenyl)-2-(trans-2-phenylcyclopropyl)pyrimidine (86 mg, 0.296mmol) in dichloromethane (0.2 mL) at 0° C. was added chlorosulfonic acid(0.20 mL, 2.99 mmol) dropwise and the reaction mixture was allowed tostir for 30 min. The reaction mixture was warmed to ambient temperatureand allowed to stir for 30 min. The reaction mixture was cooled to 0° C.and added dropwise to ice water (5 mL) and the layers separated. Theaqueous phase was extracted with dichloromethane (3×5 mL) and thecombined organic extracts concentrated under reduced pressure. Theresidue was dissolved in 1,4-dioxane (1.0 mL) and to the resultingsolution was added ammonia (7 M solution in methanol, 0.5 mL, 3.5 mmol).The reaction mixture was allowed to stir for 15 min then diluted withwater (5 mL). The layers were separated and the aqueous phase wasextracted with ethyl acetate (2×10 mL). The combined organic extractswere washed with water (10 mL) and saturated aqueous sodium chloride (10mL), dried (magnesium sulfate), and concentrated under reduced pressure.The residue was purified by silica gel chromatography, eluting with agradient of ethyl acetate:ethanol:hexanes—3:1:96 to 57:19:24 to affordthe racemic title compound. The racemate was resolved by SFC, utilizinga ChiralPak OJ-H column, eluting with methanol:carbon dioxide—30:70. Thefirst major peak to elute was4-{trans-2-[4-(3-fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,enantiomer A, the title compound and the second major peak to elute was4-{trans-2-[4-(3-fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide,enantiomer B. MS: m/z=370.1 [M+H]. ¹H NMR (600 MHz, DMSO-d₆): δ 8.79 (d,J=5.3 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 8.04 (d, J=10.2 Hz, 1H), 7.93 (d,J=5.3 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.64-7.58 (m, 1H), 7.45 (d, J=8.4Hz, 2H), 7.43-7.39 (m, 1H), 7.30 (s, 2H), 2.75-2.69 (m, 1H), 2.67-2.62(m, 1H), 1.92-1.87 (m, 1H), 1.72-1.67 (m, 1H).

Example 11

4-(trans-2-{4-[5-(Trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl)benzenesulfonamide,Enantiomer A

Essentially following the procedures described in Example 10, but using2-chloro-4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidine (Intermediate 11)in place of 2-chloro-4-(3-fluorophenyl)pyrimidine, the racemic titlecompound was obtained. The racemate was resolved by SFC, utilizing aChiralPak AS-H column, eluting with methanol:carbon dioxide—30:70. Thefirst major peak to elute was4-(trans-2-{4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl)benzenesulfonamide,enantiomer A, the title compound and the second major peak to elute was4-(trans-2-{4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl)benzenesulfonamide,enantiomer B. MS: m/z=421.0 [M+H]. ¹H NMR (600 MHz, DMSO-d₆): δ 9.68 (s,1H), 9.16 (s, 1H), 8.90 (s, 1H), 8.88 (d, J=5.2 Hz, 1H), 8.15 (d, J=5.2Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.30 (s, 2H),2.79-2.74 (m, 1H), 2.73-2.67 (m, 1H), 1.95-1.89 (m, 1H), 1.76-1.69 (m,1H).

The examples appearing in the following tables were prepared by analogyto the above examples, as described or prepared as a result of similartransformations with modifications known to those skilled in the art.The requisite starting materials were described herein, commerciallyavailable, known in the literature, or readily synthesized by oneskilled in the art. Straightforward protecting group strategies wereapplied in some routes.

TABLE EX-A

Ex- Cyclopropyl MS ample X R¹ R² R³ R⁴ Stereochemistry [M + H] A1 H i-PrH H H trans, single enantiomer 317.2 A2 H H H i-Pr H trans, singleenantiomer 317.2 A3 H H i-Pr H H trans, single enantiomer 317.2 A4 Hc-Pen H H H trans, single enantiomer 343.2 A5 H H i-Pr H H trans, singleenantiomer 317.2 A6 H H i-Pr H H trans, racemic 317.3 A7 H H H H i-Prtrans, racemic 317.3 A8 H 1-Pyrazole H H H trans, racemic 341.1 A9 H4-THP H H H trans, racemic 359.2 A10 H i-Pr H H H trans, racemic 317.3A11 H H H i-Pr H trans, racemic 317.3 A12 H c-Pen H H H trans, racemic343.3 A13 H H c-Pen H H trans, racemic 343.3

TABLE EX-B

Ex- Cyclopropyl MS ample R Stereochemistry [M + H] B1

mixture of isomers 389.2 B2

trans, racemic 318.2 B3

trans, racemic 318.2

TABLE EX-C

Cyclopropane MS Example X R¹ R² R³ Stereochemistry [M + H] C1 H H i-Pr Htrans, single 318.2 enantiomer C2 H H i-Pr H trans, racemic 318.2 C3 Hi-Pr H H trans, racemic 318.2 C4 H 3-fluorophenyl H H trans, enantiomerB 370.1 C5 H 5-(trifluoromethyl) H H trans, enantiomer B 421.1pyridin-3-yl C6 F 3-fluorophenyl H H 1R,3R 406.2

TABLE EX-D

Cyclopropane Example X R¹ R² R³ Stereochemistry MS [M + H] D1 H

H H trans, racemic 319.3 D2 H

H H trans, racemic 358.1 D3 H

H H trans, racemic 380.1 D4 H

H H trans, racemic 459.2 D5 H

H H trans, racemic 360.1 D6 H

H H trans, racemic 380.1 D7 H

H H trans, racemic 344.1 D8 H

H H trans, racemic 384.1 D9 H

H H trans, racemic 352.1 D10 H

H H trans, racemic 395.2 D11 H

H H trans, racemic 367.1

TABLE EX-E

Cyclopropane MS Example X R¹ R² R³ R⁴ Stereochemistry [M + H] E1 H Hi-Pr H H trans, racemic 317.2 E2 H H i-Pr H H trans, racemic 317.2 E3 HH c-Bu H H trans, racemic 329.1

TABLE EX-F

Cyclopropane MS Example X R¹ R² R³ R⁴ R⁵ Stereochemistry [M + H] F1 H HH 1-Imidazole H H trans, racemic 340.1 F2 H H

H H H trans, racemic 341.1

TABLE EX-G

Ex- Cyclopropane MS ample X R¹ R² R³ R⁴ Stereochemistry [M + H] G1 H Hi-Pr H H trans, racemic 317.1 G2 H H H

H trans, racemic 344.1 G3 H H 1-Pyrazole H H trans, racemic 341.1 G4 H HOi-Pr H H trans, racemic 333.1 G5 H H CMe₂CN H H trans, racemic 342.1

The utility of the compounds in accordance with the present invention aspositive allosteric modulators of π7 nicotinic acetylcholine receptoractivity may be demonstrated by methodology known in the art. Directactivation of π7 (agonism), and potentiation of acetylcholine-evoked π7currents was determined as follows:

Automated Patch-Clamp Electrophysiology Functional Assay (Assay A)

Automated patch-clamp electrophysiology was performed using the IonFluxHT (Fluxion Biosciences Inc., San Francisco, Calif.) in the whole-cell,population patch configuration. Test compounds were assessed for theirability to modulate the function of the π7 nicotinic acetylcholinereceptor both in the presence, and in the absence of the natural π7agonist acetylcholine. A HEK cell line stably expressing both humanRIC-3 and human π7 (PrecisION hnAChR π7/RIC-3, Eurofins Pharma, St.Charles, Mo.) was cultured in 175 cm² triple-layer tissue culture flasksto no more than 90% confluency in DMEM/F-12 growth media supplementedwith 10% heat-inactivated fetal bovine serum, 1% non-essential aminoacids, 0.625 μg/mL Puromycin, and 400 μg/mL Geneticin. Immediately priorto assay, cells were detached by first aspirating growth media, rinsingwith Dulbecco's phosphate buffered saline, and then adding 10 mL ofAccutase (Innovative Cell Technologies, San Diego, Calif.) to the flaskand then incubating at 37° C. for 5 minutes. Detached cells were thenrecovered by the addition of 40 mL of CHO-serum-free media supplementedwith 25 mM HEPES, and rocked gently in a 50 mL conical tube for 20minutes prior to patch-clamp assay. After recovery, cells were pelletedby centrifugation at 1,000 RPM for 1 minute in a compact bench topcentrifuge; recovery media was aspirated and cells were resuspended inexternal recording solution (150 mM NaCl, 5 mM KCl, 2 mM CaCl₂), 1 mMMgCl₂, 10 mM HEPES, 12 mM dextrose) to a density of 5.0×10⁶ cells/mL.The cell suspension was added to the cell inlet wells on an IonFlux HTpopulation patch plate which had previously been rinsed and primed withdeionized H₂O. Test compounds were serially diluted in DMSO and thenresuspended to the final test concentration in external recordingsolution, with, or without 40 μM acetylcholine added to the externalrecording solution; test compounds were then transferred to the IonFluxHT population patch plate. Internal recording solution (110 mM TrisPO₄,28 mM TrisBase, 0.1 mM CaCl₂, 2 mM MgCl₂, 11 mM EGTA, 4 mM MgATP) wasadded to the internal recording solution inlet wells on the IonFlux HTpatch plate previously loaded with cells and test compounds, and theplate loaded into the IonFlux HT instrument. A protocol was executed onthe IonFlux HT to trap the cells, break into the cells, and establishthe whole-cell recording configuration; cells were voltage-clamped at aholding potential of −60 mV for the duration of the experiment, allexperiments were conducted at room temperature, and the IonFlux HTinjection pressure was 8 psi for solution applications. Uponestablishing the whole-cell configuration, external recording solutionwas perfused into the recording chambers for 120 seconds and then 40 μMacetylcholine was applied for 1 second and immediately washed off withexternal recording solution for 60 seconds. The 40 μMacetylcholine-evoked π7 current served as the current response to whichsubsequent test compound effects, in the presence, or in the absence of40 μM acetylcholine would be quantified relative to. Next, testcompounds were evaluated at multiple concentrations for their ability toinduce, or modulate π7 current responses; three concentrations of testcompound were evaluated in ascending dose fashion per recording. Toassess test compound agonist activity, test compound diluted in externalrecording solution was applied starting from the lowest concentration oftest compound being tested in the concentration series, for 58 seconds;the first 20 seconds of the 58 second compound application periodcoincided with a data collection sweep which was 20 seconds in duration,and collected at a rate of 5,000 samples/second. To assess test compoundpositive allosteric modulator activity, immediately following the 58second test compound only application period, the same concentration oftest compound, diluted in external recording solution containing 40 μMacetylcholine was applied for 1 second; in this way, the test compoundand the natural receptor agonist acetylcholine were co-applied, andpotentiating effects of test compounds observed. The 1 secondapplication of test compound diluted in external solution containing 40μM acetylcholine coincided with a data collection sweep which was 20seconds in duration, and collected at a rate of 5,000 samples/second,after which, external recording solution only was applied for 42seconds. Following this 42 second wash with external recording solutiononly, the next highest concentration of the test compound in theconcentration series was applied in the absence and then in the presenceof acetylcholine as previously described, and data collected aspreviously described. After test compound agonist, and positiveallosteric modulator activity were assessed at three ascendingconcentrations, the experiment was terminated and leak subtractionperformed using the IonFlux HT data analysis software. Peak currentamplitudes and the area under the curve (AUC) were both quantified foreach current sweep using proprietary software and test compound effectswhere quantified as follows.

Test compound agonist activity was calculated as:% Agonism=(Y/X)×100Test compound potentiator activity was calculated as:% Potentiation=[(Z/X)×100]−100

-   -   X=Peak current amplitude (or AUC) evoked by 40 μM acetylcholine    -   Y=Peak current amplitude (or AUC) evoked by test compound        diluted in external recording solution    -   Z=Peak current amplitude (or AUC) evoked by test compound        diluted in external recording solution containing 40 μM        acetylcholine

As such, test compounds which evoked the same current amplitude as 40 μMacetylcholine alone would exhibit a calculated % Agonism of 100%. Testcompounds co-applied with 40 μM acetylcholine which evoked a currentamplitude 2× the current evoked from 40 μM acetylcholine alone wouldexhibit a calculated % Potentiation of 100%, whereas test compoundsco-applied with 40 μM acetylcholine which evoked the same currentamplitude as 40 μM acetylcholine alone would be characterized asexhibiting no potentiation.

Agonist and potentiation data, derived by peak current amplitude or areaunder the curve (AUC) were graphed and fit using a 4-parameter logisticfit based on the Levenberg-Marquardt algorithm wherey=A+((B−A)/(1+((C/x){circumflex over ( )}D))) where:

-   -   A=Minimum    -   B=Maximum    -   C=EC₅₀    -   D=Slope    -   x=test compound concentration    -   y=% Agonism or % Potentiation

Potency data for selected compounds of the present invention in theautomated patch-clamp electrophysiology functional assay (Assay A) arerepresented in the table below:

Example α7 nAChR Potency Example α7 nAChR Potency 1 B 2 C 3 C C2 C 4 CC3 C 5 B C4 C 6 C C5 C 7 B C6 C 8 C D1 C 9 C D2 C 10 B D3 C 11 B D4 C A1C D5 C A2 B D6 C A3 C D7 C A4 C D8 C A5 C D9 C A6 C D10 C A7 C D11 C A8C E1 C A9 D E2 C A10 C E3 B A11 B F1 C A12 B F2 D A13 C G1 C B1 C G2 CB2 D G3 C B3 C G4 C C1 B G5 C *Potency defined as A (EC₅₀ ≤ 0.1 μM); B(0.1 μM < EC₅₀ ≤ 0.5 (μM); C (0.5 μM < EC₅₀ ≤ 5 (μM); D (5 μM < EC₅₀ ≤50 (μM)

Electrophysiology EC₅₀ values for selected compounds of the presentinvention in the automated patch-clamp electrophysiology functionalassay (Assay A) are provided in the table below:

Example α7 nAChR EC₅₀ (nM) Example α7 nAChR EC₅₀ (nM) 1 500 C1 280 22000 C3 1800 3 1500 C4 1900 4 1000 C5 3300 5 410 C6 1600 6 720 D1 2900 7320 D2 2200 8 1200 D4 720 9 1400 D5 1800 10 210 D7 900 11 240 D8 3800 A2410 D10 1100 A3 550 D11 3300 A6 700 E3 500 A7 2400 F1 3700 A8 3300 F25200 A9 5600 G2 3200 A11 460 G3 870 A13 1500 G4 1000 B1 1600 G5 3400 B28800

It will be appreciated that various of the above-discussed and otherfeatures and functions, or alternatives thereof, may be desirablycombined into many other different systems or applications. Also thatvarious presently unforeseen or unanticipated alternatives,modifications, variations or improvements therein may be subsequentlymade by those skilled in the art which are also intended to beencompassed by the following claims.

What is claimed is:
 1. A compound, having the formula:

or a pharmaceutically acceptable salt thereof, wherein; A is phenylsubstituted with 1 R group selected from (C₁-C₆)alkyl, O(C₁-C₆)alkyl,NR⁷R⁸, (C₃-C₆)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein theR group is optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CN, (C₁-C₄)alkyl,(C═O)O(C₁-C₄)alkyl and phenyl; R³ is H or Si(CH₃)₃; R⁴ is H; and R⁷ andR⁸ are independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,aryl, heteroaryl and heterocyclyl, wherein each alkyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents independently selected from halogen and phenyl.
 2. Thecompound of claim 1 having the formula Ia, or a pharmaceuticallyacceptable salt thereof, wherein; A is phenyl substituted with 1 R groupselected from (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NR⁷R⁸, cyclobutyl,cyclopentyl, phenyl, pyridinyl, morpholinyl, imidazolyl, pyrazolyl,oxadiazolyl, pyrrolidinyl, piperazinyl, triazolyl and tetrahydropyranylwherein the R group is optionally substituted with one or moresubstituents independently selected from halogen, CF₃, CN, (C₁-C₄)alkyl,(C═O)O(C₁-C₄)alkyl and phenyl; R³ is H or Si(CH₃)3; R⁴ is H; and R⁷ andR⁸ are independently selected from H, (C₁-C₆)alkyl, cyclopentyl andphenyl, wherein each alkyl, cyclopentyl, and phenyl are optionallysubstituted with one or more substituents independently selected fromhalogen and phenyl.
 3. The compound of claim 1 which is selected fromthe group consisting of4-{trans-2-[3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]cyclopropyl}benzenesulfonamide;4-{trans-2-[4-(1H-Imidazol-1-yl)phenyl]cyclopropyl}benzenesulfonamide;and4-{trans-2-[3-(1H-1,2,4-Triazol-1-yl)phenyl]cyclopropyl}benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising (i) a pharmaceutically acceptable carrier and(ii) a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 5. The pharmaceutical composition of claim 4, furthercomprising a second therapeutic agent selected from the group consistingof acetylcholinesterase inhibitors; NMDA receptor antagonists;antipsychotics; MAO-B inhibitors; and levodopa.
 6. A method of treatinga patient with cognitive impairments associated with Alzheimer'sdisease, Parkinson's disease, and schizophrenia, the method comprisingadministering to the patient the compound of claim 1, or apharmaceutically acceptable salt thereof, in an amount effective totreat the patient.
 7. A method for modulating α7 nAChR activity in asubject in need thereof, comprising administering a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.